Chapel Hill, NC, United States
Chapel Hill, NC, United States

The University of North Carolina at Chapel Hill is a coeducational public research university located in Chapel Hill, North Carolina, United States. North Carolina has been consistently listed among the highest and best ranked universities in the United States and is one of the original eight Public Ivy schools that provide an Ivy League experience for a public schooling price. After being chartered in 1789, the university first began enrolling students in 1795, which allows it to be one of three schools to claim the title of the oldest public university in the United States.The first public institution of higher education in North Carolina, the school opened its doors to students on February 12, 1795. The university offers degrees in over 70 courses of study through fourteen colleges and the College of Arts and science. All undergraduates receive a liberal arts education and have the option to pursue a major within the professional schools of the university or within the College of Arts and science from the time they obtain junior status. Under the leadership of President Kemp Plummer Battle, in 1877 North Carolina became coeducational and began the process of desegregation in 1951 when African-American graduate students were admitted under Chancellor Robert Burton House. In 1952, North Carolina opened its own hospital, UNC Health Care, for research and treatment, and has since specialized in cancer care. The school's students, alumni, and sports teams are known as "Tar Heels".The campus of North Carolina is located in Chapel Hill, North Carolina, a university town. The campus covers a rather small 729 acres over Chapel Hill's downtown area, encompassing places like the Morehead Planetarium and the many stores and shops located on Franklin Street. Students can participate in over 550 officially recognized student organizations. The student-run newspaper The Daily Tar Heel has won national awards for collegiate media, while the student radio station WXYC provided the world's first internet radio broadcast. North Carolina is one of the charter members of the Atlantic Coast Conference, which was founded on June 14, 1953. Competing athletically as the Tar Heels, North Carolina has achieved great success in sports, most notably in men's basketball, women's soccer, and women's field hockey. Wikipedia.


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Patent
University of North Carolina at Chapel Hill | Date: 2016-12-06

The present invention relates to the ability of PLUNC proteins, such as SPLUNC1 and SPLUNC2, to bind to sodium channels and inhibit activation of the sodium channels. The invention further relates to methods for regulating of sodium absorption and fluid volume and treating disorders responsive to modulating sodium absorption by modulating the binding of PLUNC proteins to sodium channels.


Patent
University of North Carolina at Chapel Hill | Date: 2016-12-09

The present invention relates to trisodium diethylenetriamine pentaacetic acid (DTPA) prodrugs, such as, for example, DTPA di-ethyl esters. The invention further relates to compositions comprising DTPA prodrugs and methods of using the same.


Patent
University of Washington, University of North Carolina at Chapel Hill and University of Utah | Date: 2016-02-12

Disclosed are compositions and methods related intrinsic gene sets and methods and compositions related to detecting and classifying cancer.


Patent
University of North Carolina at Chapel Hill | Date: 2015-04-14

An organometallic complex of a tridentate bis(phosphine)-carbodicarbene ligand and a transition metal, is described. In some embodiments the ligand has the structure of Formula (I): The complexes are useful in methods of making an allylic amine carried out by reacting a 1,3-diene with a substituted amine in the presence of such an organometallic complex to produce by intermolecular hydroamination the allylic amine.


Patent
University of North Carolina at Chapel Hill | Date: 2015-03-13

Compounds suitable for use in providing male contraception, an assay method for identifying such compounds, and methods of providing contraception using the compounds, are provided. In one embodiment, the compounds described herein mimic the binding of anti-EPPIN antibodies to EPPIN, and thus inhibit the forward motility of sperm in humans and other primates. In another embodiment, the compounds described herein inhibit or enhance EPPIN-semenogelin binding, and inhibit forward motility of sperm. The assays described herein identify compounds which inhibit sperm motility, and can be carried out in a high throughput manner, using labeled recombinant EPPIN and semenogelin. The compounds can be used in oral or transdermal compositions to temporarily and reversibly inhibit male fertility. They can also be used in addition to, or in place of, spermicides in spermicidal compositions, such as those used in conjunction with condoms, diaphragms, and spermicidal jellies.


Patent
University of North Carolina at Chapel Hill and Greenville Health System | Date: 2015-03-19

Methods for identifying subjects as candidates for embryo implantation are provided. In some embodiments, the methods include providing a sample of endometrium isolated from a subject during the second half of the subjects menstrual cycle and determining whether the subject is a candidate based on the expression of BCL6 in the sample. Also provided are methods for identifying an increased risk for implantation failure subsequent to in vitro fertilization (IVF) and/or frozen embryo transfer (FET), methods for detecting endometrial receptivity, methods for facilitating diagnoses of infertility, methods for increasing the likelihood of embryo implantation, methods for detecting the presence of endometriosis, and methods for managing treatment of subjects with potential endometriosis, subfertility, or both.


Methods, systems, and computer readable media for utilizing adaptive rectangular decomposition (ARD) to perform head-related transfer function (HRTF) simulations are disclosed herein. According to one method, the method includes obtaining a mesh model representative of head and ear geometry of a listener entity and segmenting a simulation domain of the mesh model into a plurality of partitions. The method further includes conducting an ARD simulation on the plurality of partitions to generate simulated sound pressure signals within each of the plurality of partitions and processing the simulated sound pressure signals to generate at least one HRTF that is customized for the listener entity.


Patent
Entegrion and University of North Carolina at Chapel Hill | Date: 2017-02-22

The present invention is directed to a hemostatic textile, comprising: a material comprising a combination of glass fibers and one or more secondary fibers selected from the group consisting of silk fibers; ceramic fibers; raw or regenerated bamboo fibers; cotton fibers; rayon fibers; linen fibers; ramie fibers; jute fibers; sisal fibers; flax fibers; soybean fibers; corn fibers; hemp fibers; lyocel fibers; wool; lactide and/or glycolide polymers; lactide/glycolide copolymers; silicate fibers; polyamide fibers; feldspar fibers; zeolite fibers, zeolite-containing fibers, acetate fibers; and combinations thereof; the hemostatic textile capable of activating hemostatic systems in the body when applied to a wound. Additional cofactors such as thrombin and hemostatic agents such as RL platelets, RL blood cells; fibrin, fibrinogen, and combinations thereof may also be incorporated into the textile. The invention is also directed to methods of producing the textile, and methods of using the textile to stop bleeding. (Drawing Figure 1)


Moss L.A.,Injury Prevention Research Center | Skelton J.A.,University of North Carolina at Chapel Hill
New England Journal of Medicine | Year: 2015

BACKGROUND The prevalence of severe obesity among children and young adults has increased over the past decade. Although the prevalence of cardiometabolic risk factors is relatively low among children and young adults who are overweight or obese, those with more severe forms of obesity may be at greater risk. METHODS We performed a cross-sectional analysis of data from overweight or obese children and young adults 3 to 19 years of age who were included in the National Health and Nutrition Examination Survey from 1999 through 2012 to assess the prevalence of multiple cardiometabolic risk factors according to the severity of obesity. Weight status was classified on the basis of measured height and weight. We used standard definitions of abnormal values for total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, triglycerides, blood pressure, glycated hemoglobin, and fasting glucose and report the prevalence of abnormal values in children and young adults according to weight status. RESULTS Among 8579 children and young adults with a body-mass index at the 85th percentile or higher (according to the Centers for Disease Control and Prevention growth charts), 46.9% were overweight, 36.4% had class I obesity, 11.9% had class II obesity, and 4.8% had class III obesity. Mean values for some, but not all, cardiometabolic variables were higher with greater severity of obesity in both male and female participants, and the values were higher in male participants than in female participants; for HDL cholesterol, the mean values were lower with greater severity of obesity. Multivariable models that controlled for age, race or ethnic group, and sex showed that the greater the severity of obesity, the higher the risks of a low HDL cholesterol level, high systolic and diastolic blood pressures, and high triglyceride and glycated hemoglobin levels. CONCLUSIONS Severe obesity in children and young adults was associated with an increased prevalence of cardiometabolic risk factors, particularly among boys and young men. © 2015 Massachusetts Medical Society. All rights reserved.


Roth B.L.,University of North Carolina at Chapel Hill
Annual Review of Pharmacology and Toxicology | Year: 2015

In the past decade, emerging synthetic biology technologies such as chemogenetics have dramatically transformed how pharmacologists and systems biologists deconstruct the involvement of G protein-coupled receptors (GPCRs) in a myriad of physiological and translational settings. Here we highlight a specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): We have dubbed it DREADDs (designer receptors exclusively activated by designer drugs). As we show in this review, DREADDs are now used ubiquitously to modulate GPCR activity noninvasively in vivo. Results from these studies have directly implicated GPCR signaling in a large number of therapeutically relevant contexts. We also highlight recent applications of DREADD technology that have illuminated GPCR signaling processes that control pathways relevant to the treatment of eating disorders, obesity, and obesity-associated metabolic abnormalities. Additionally, we provide an overview of the potential utility of chemogenetic technologies for transformative therapeutics. ©2015 by Annual Reviews. All rights reserved.


Matera A.G.,University of North Carolina | Wang Z.,University of North Carolina at Chapel Hill
Nature Reviews Molecular Cell Biology | Year: 2014

One of the most amazing findings in molecular biology was the discovery that eukaryotic genes are discontinuous, with coding DNA being interrupted by stretches of non-coding sequence. The subsequent realization that the intervening regions are removed from pre-mRNA transcripts via the activity of a common set of small nuclear RNAs (snRNAs), which assemble together with associated proteins into a complex known as the spliceosome, was equally surprising. How do cells coordinate the assembly of this molecular machine? And how does the spliceosome accurately recognize exons and introns to carry out the splicing reaction? Insights into these questions have been gained by studying the life cycle of spliceosomal snRNAs from their transcription, nuclear export and re-import to their dynamic assembly into the spliceosome. This assembly process can also affect the regulation of alternative splicing and has implications for human disease. © 2014 Macmillan Publishers Limited.


Perou C.M.,University of North Carolina at Chapel Hill | Borresen-Dale A.-L.,University of Oslo
Cold Spring Harbor Perspectives in Biology | Year: 2011

It is now accepted that breast cancer is not a single disease, but instead it is composed of a spectrum of tumor subtypes with distinct cellular origins, somatic changes, and etiologies. Gene expression profiling using DNA microarrays has contributed significantly to our understanding of the molecular heterogeneity of breast tumor formation, progression, and recurrence. For example, at least two clinical diagnostic assays exist (i.e., OncotypeDX RS and Mammaprint®) that are able to predict outcome in patients using patterns of gene expression and predetermined mathematical algorithms. In addition, a new molecular taxonomy based upon the inherent, or "intrinsic," biology of breast tumors has been developed; this taxonomy is called the "intrinsic subtypes of breast cancer," which now identifies five distinct tumor types and a normal breast-like group. Importantly, the intrinsic subtypes of breast cancer predict patient relapse, overall survival, and response to endocrine and chemotherapy regimens. Thus, most of the clinical behavior of a breast tumor is already written in its subtype profile. Here, we describe the discovery and basic biology of the intrinsic subtypes of breast cancer, and detail how this interacts with underlying genetic alternations, response to therapy, and the metastatic process. © 2011 Cold Spring Harbor Laboratory Press.


Patent
INC Research, University of Michigan and University of North Carolina at Chapel Hill | Date: 2014-07-21

Although it can be farnesylated, the mutant lamin A protein expressed in Hutchinson Gilford Progeria Syndrome (HGPS) cannot be defarnesylated because the characteristic mutation causes deletion of a cleavage site necessary for binding the protease ZMPSTE24 and effecting defarnesylation. The result is an aberrant farnesylated protein (called progerin) that alters normal lamin A function as a dominant negative, as well as assuming its own aberrant function through its association with the nuclear membrane. The retention of farnesylation, and potentially other abnormal properties of progerin and other abnormal lamin gene protein products, produces disease. Farnesyltransferase inhibitors (FTIs) (both direct effectors and indirect inhibitors) will inhibit the formation of progerin, cause a decrease in lamin A protein, and/or an increase prelamin A protein. Decreasing the amount of aberrant protein improves cellular effects caused by and progerin expression. Similarly, treatment with FTIs should improve disease status in progeria and other laminopathies. In addition, elements of atherosclerosis and aging in non-laminopathy individuals will improve after treatment with farnesyltransferase inhibitors.


Patent
University of North Carolina at Chapel Hill, University of Michigan and INC Research | Date: 2013-04-04

Although it can be farnesylated, the mutant lamin A protein expressed in Hutchinson Gilford Progeria Syndrome (HGPS) cannot be defarnesylated because the characteristic mutation causes deletion of a cleavage site necessary for binding the protease ZMPSTE24 and effecting defarnesylation. The result is an aberrant farnesylated protein (called progerin) that alters normal lamin A function as a dominant negative, as well as assuming its own aberrant function through its association with the nuclear membrane. The retention of farnesylation, and potentially other abnormal properties of progerin and other abnormal lamin gene protein products, produces disease. Farnesyltransferase inhibitors (FTIs) (both direct effectors and indirect inhibitors) will inhibit the formation of progerin, cause a decrease in lamin A protein, and/or an increase prelamin A protein. Decreasing the amount of aberrant protein improves cellular effects caused by and progerin expression. Similarly, treatment with FTIs should improve disease status in progeria and other laminopathies. In addition, elements of atherosclerosis and aging in non-laminopathy individuals will improve after treatment with farnesyltransferase inhibitors.


Patent
University of North Carolina at Chapel Hill and The Regents Of The University Of California | Date: 2013-04-17

Methods and compounds for treating neurological and other disorders are provided. Included is the administering to a subject in need thereof an effective amount of a compound having binding and/or modulation specificity for a TrkB receptor molecule.


Patent
University of North Carolina at Chapel Hill and The Regents Of The University Of California | Date: 2014-01-27

Methods and compounds for treating neurological and other disorders are provided. Included is the administering to a subject in need thereof an effective amount of a compound having binding and/or modulation specificity for a TrkB receptor molecule.


Grant
Agency: Cordis | Branch: H2020 | Program: RIA | Phase: SC1-PM-22-2016 | Award Amount: 12.56M | Year: 2016

The ZikaPLAN initiative combines the strengths of 25 partners in Latin America, North America, Africa, Asia, and various centres in Europe to address the urgent research gaps (WP 1-8) in Zika, identifying short-and long term solutions (WP 9-10) and building a sustainable Latin-American EID Preparedness and Response capacity (WP 11-12). We will conduct clinical studies to further refine the full spectrum and risk factors of congenital Zika syndrome (including neurodevelopmental milestones in the first 3 years of life), and delineate neurological complications associated with Zika due to direct neuroinvasion and immune-mediated responses. Laboratory based research to unravel neurotropism, investigate the role of sexual transmission, determinants of severe disease, and viral fitness will envelop the clinical studies. Burden of disease and modelling studies will assemble a wealth of data including a longitudinal cohort study of 17,000 subjects aged 2-59 in 14 different geographic locations in Brazil over 3 years. Data driven vector control and vaccine modelling as well as risk assessments on geographic spread of Zika will form the foundation for evidence-informed policies. The Platform for Diagnostics Innovation and Evaluation will develop novel ZIKV diagnostic tests in accordance with WHO Target Product Profiles. Our global network of laboratory and clinical sites with well-characterized specimens is set out to accelerate the evaluation of the performance of such tests. Based on qualitative research, we will develop supportive, actionable messages to affected communities, and develop novel personal protective measures. Our final objective is for the Zika outbreak response effort to grow into a sustainable Latin-American network for emerging infectious diseases research preparedness. To this end we will engage in capacity building in laboratory and clinical research, collaborate with existing networks to share knowledge and tackle regulatory and other bottlenecks.


Rogan S.C.,University of North Carolina at Chapel Hill | Roth B.L.,University of North Carolina at Chapel Hill | Roth B.L.,National Institute of Mental Health Psychoactive Drug Screening Program
Pharmacological Reviews | Year: 2011

A significant challenge for neuroscientists is to determine how both electrical and chemical signals affect the activity of cells and circuits and how the nervous system subsequently translates that activity into behavior. Remote, bidirectional manipulation of those signals with high spatiotemporal precision is an ideal approach to addressing that challenge. Neuroscientists have recently developed a diverse set of tools that permit such experimental manipulation with varying degrees of spatial, temporal, and directional control. These tools use light, peptides, and small molecules to primarily activate ion channels and G protein-coupled receptors (GPCRs) that in turn activate or inhibit neuronal firing. By monitoring the electrophysiological, biochemical, and behavioral effects of such activation/inhibition, researchers can better understand the links between brain activity and behavior. Here, we review the tools that are available for this type of experimentation. We describe the development of the tools and highlight exciting in vivo data. We focus primarily on designer GPCRs (receptors activated solely by synthetic ligands, designer receptors exclusively activated by designer drugs) and microbial opsins (e.g., channelrhodopsin-2, halorhodopsin, Volvox carteri channelrhodopsin) but also describe other novel techniques that use orthogonal receptors, caged ligands, allosteric modulators, andother approaches. These tools differ in the direction of their effect (activation/inhibition, hyperpolarization/ depolarization), their onset and offset kinetics (milliseconds/ minutes/hours), the degree of spatial resolution they afford, and their invasiveness. Although none of these tools is perfect, each has advantages and disadvantages, which we describe, and they are all still works in progress. We conclude with suggestions for improving upon the existing tools.


Anderson M.S.,University of California at San Francisco | Su M.A.,University of North Carolina at Chapel Hill
Current Opinion in Immunology | Year: 2011

In the thymus, developing T cells that react against self-antigens with high affinity are deleted in the process of negative selection. An essential component of this process is the display of self-antigens, including those whose expression are usually restricted to specific tissues, to developing T cells within the thymus. The Autoimmune Regulator (Aire) gene plays a crucial role in the expression of tissue specific self-antigens within the thymus, and disruption of Aire function results in spontaneous autoimmunity in both humans and mice. Recent advances have been made in our understanding of how Aire influences the expression of thousands of tissue-specific antigens in the thymus. Additional roles of Aire, including roles in chemokine and cytokine expression, have also been revealed. Factors important in the differentiation of Aire-expressing medullary thymic epithelial cells have been defined. Finally, the identity of antigen presenting cells in negative selection, including the role of medullary thymic epithelial cells in displaying tissue specific antigens to T cells, has also been clarified. © 2010 Elsevier Ltd.


Kahn R.,University of North Carolina at Chapel Hill | Davidson M.B.,Drew University
Diabetes Care | Year: 2014

Efforts to reduce the burden of type 2 diabetes include attempts to prevent or delay the onset of the disease. Landmark clinical trials have shown that lifestyle modification programs focused on weight loss can delay the onset of type 2 diabetes in subjects at high risk of developing the disease. Building on this knowledge, many community-based studies have attempted to replicate the trial results and, simultaneously, payers have begun to cover diabetes prevention services. This article focuses on the evidence supporting the premise that community prevention efforts will be successful. Unfortunately, no study has shown that diabetes can be delayed or prevented in a community setting, and efforts to replicate the weight loss achieved in the trials have been mostly disappointing. Furthermore, both the clinical trials and the community-based prevention studies have not shown a beneficial effect on any diabetes-related clinical outcome. While the goal of diabetes prevention is extremely important, the absence of any persuasive evidence for the effectiveness of community programs calls into question whether the use of public funds or national prevention initiatives should be supported at this time. © 2014 by the American Diabetes Association.


Hurlbert A.H.,University of North Carolina at Chapel Hill | Stegen J.C.,Pacific Northwest National Laboratory
Ecology Letters | Year: 2014

Energetic constraints are fundamental to ecology and evolution, and empirical relationships between species richness and estimates of available energy (i.e. resources) have led some to suggest that richness is energetically constrained. However, the mechanism linking energy with richness is rarely specified and predictions of secondary patterns consistent with energy-constrained richness are lacking. Here, we lay out the necessary and sufficient assumptions of a causal relationship linking energy gradients to richness gradients. We then describe an eco-evolutionary simulation model that combines spatially explicit diversification with trait evolution, resource availability and assemblage-level carrying capacities. Our model identified patterns in richness and phylogenetic structure expected when a spatial gradient in energy availability determines the number of individuals supported in a given area. A comparison to patterns under alternative scenarios, in which fundamental assumptions behind energetic explanations were violated, revealed patterns that are useful for evaluating the importance of energetic constraints in empirical systems. We use a data set on rockfish (genus Sebastes) from the northeastern Pacific to show how empirical data can be coupled with model predictions to evaluate the role of energetic constraints in generating observed richness gradients. © 2014 John Wiley & Sons Ltd/CNRS.


Grant
Agency: Cordis | Branch: H2020 | Program: RIA | Phase: EINFRA-7-2014 | Award Amount: 3.46M | Year: 2015

Five years ago, a global infrastructure to uniquely attribute to researchers their scientific artefacts (articles, data, software) appeared technically and socially infeasible. Since then, DataCite has minted over 3.5m unique identifiers for data. ORCID has deployed an open solution for identification of contributors with over 850,000 registrants in less than 2 years. THOR will leverage these emerging global infrastructures to support the H2020 goal to make every researcher digital and increase creativity and efficiency of research, while bridging the R&D divide between developed and less-developed regions. We will establish interoperability between existing resources, linking digital identifiers across platforms and propagating attribution information. We will integrate PID services across the research lifecycle and data publishing workflows in four advanced research communities, and then roll-out core services and service building blocks for the wider community. These open resources will foster an open and sustainable e-infrastructure across stakeholders to avoid duplications, give economies of scale, richness of services and the ability to respond rapidly to opportunities for innovation. THOR is not just relevant to the EINFRA-7-1024 Call, but will become a pervasive element of the EINFRA family of e-Infrastructure resources over the next 3 years. It will allow data-management and curation services to exploit knowledge of data location and attribution; provide robust and persistent mechanism for linking literature and data; enable search and resolving services and generate incentives for Open Science; deliver provenance and attribution mechanisms to underpin data exchange; and provide minting and resolving services for data citation workflows. Its impact will enable third-party services, no-profit and commercial, to leverage the scholarly record.


Patent
University of Illinois at Urbana - Champaign and University of North Carolina at Chapel Hill | Date: 2014-12-19

The present invention relates generally to a system and methods for measuring physiological parameters. More specifically, the present invention relates to a noncontact technology by which one or more physiological parameters of a subject may be efficiently and quickly detected. Among other advantages, the present invention can be used to assess and monitor vital signs of one or more subjects in a variety of contexts including for medical or security triage purposes, for use in healthcare waiting rooms, as part of human imaging systems, or during surgery.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 312.03K | Year: 2015

DESCRIPTION provided by applicant Antisense and siRNA oligonucleotides offer the promise of highly precise manipulation of genes involved in disease pathogenesis However despite the investment of enormous resources that promise has been fulfilled to only a limited degree A key impediment to oligonucleotide based therapeutics is the difficulty in delivering these large highly polar molecules to their sites of action in the cytosol or nucleus of tissue cells While chemical modification of oligonucleotides and the utilization of various nanotechnology based delivery approaches have been helpful the delivery problem remains challenging Much of the oligonucleotide accumulated by cells remains non productively entrapped in endosomes The complex pathways of endocytosis and intracellular trafficking are being increasingly understood at the molecular level however there is a paucity of small molecule probes for these pathways Here we describe a novel technology based on the use of small organic molecules to enhance the functional delivery and pharmacological effectiveness of oligonucleotides by manipulating their intracellular trafficking We have established a proof of principle for this strategy by identifying compounds using a high throughout screen of andgt small molecules Three distinct compound series were discovered from this screen that significantly enhance oligonucleotide effects in cell culture and in one case in a transgenic mouse model We now propose medicinal chemistry efforts to build structure activity relationships and improve both potency and pharmacological properties with the end goal of creating molecules that can effectively and safely be used in vivo Promising leads will be examined for their pharmacokinetic and biodistribution behavior Finally these leads will be evaluated in a xenograft tumor model The identification of potent and non toxic enhancing molecules will likely have a major impact on the entire field of oligonucleotide therapeutics PUBLIC HEALTH RELEVANCE A key impediment to oligonucleotide based therapeutics is the difficulty in delivering these large highly polar molecules to their sites of action in the cyosol or nucleus of tissue cells While chemical modification of oligonucleotides and the utilization of various nanotechnology based delivery approaches have been helpful the delivery problem remains largely unresolved We have taken an orthogonal approach to this problem and have developed small molecule compounds that enhance the functional delivery and pharmacological effectiveness of oligonucleotides by manipulating their intracellular trafficking Here we propose to optimize compounds as in vivo probes it seems likely that this effort will have a major impact on the entire field of oligonucleotide therapeutics


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.2.4.4-2 | Award Amount: 3.85M | Year: 2012

Primary Ciliary Dyskinesia (PCD) is a rare genetically heterogeneous disorder which results from dysfunction of motile hair-like organelles (cilia) that results in severe, chronic airways disease. Due to other cilia-related disease mechanisms several other organ systems like the heart can be affected. The complexity of the disease phenotype, late diagnosis, as well as lack of evidence based management guidelines contribute to a high burden of disease and cause high health care costs. Therefore, there is a great need for observational trials as well as well-designed randomised controlled trials to put evidence-based diagnostic and treatment approaches into effect. The main objective of our project is to improve diagnosis and treatment of PCD patients. To accomplish this, we propose to: 1) Establish widespread, early diagnosis by introduction of nasal Nitric Oxide measurement as screening tool, and by introduction of high-speed videomicroscopy as diagnostic tool; 2) Develop new outcome criteria, especially a PCD-specific quality of life questionnaire, as a prerequisite for controlled PCD trials; 3) Establish a PCD registry for both cross-sectional analysis of current disease status and longitudinal observational analysis of disease progression under different regimens; 4) Generate evidence-based treatment guidelines by conducting two prospective randomized trials on the inhalation of hypertonic saline and long term azithromycin therapy. To achieve these goals members of the European Respiratory Societys PCD task force will join forces with members of the NIH-funded US-PCD-network. In our multi-national project, we will for the first time establish evidence-based guidelines for diagnosis, clinical management and therapy. We expect that in a high proportion of children the diagnosis will be established before irreversible lung damage has occurred. In later diagnosed individuals the disease burden will be reduced and chronic respiratory failure retarded.


Overstreet D.H.,University of North Carolina at Chapel Hill | Wegener G.,Aarhus University Hospital | Wegener G.,North West University South Africa
Pharmacological Reviews | Year: 2013

Approximately 25 years have passed since the first publication suggesting the Flinders sensitive line (FSL) rat as an animal model of depression. At least 6 years of research on these rats was completed before that seminal paper, and there has been a steady stream of publications (130+) over the years. The present review will focus on several issues not previously covered in earlier reviews, summarize the several lines of ongoing investigations, and propose a novel mechanism that accounts for a number of previously unexplained observations. A key observation in the FSL rat relates to the antidepressant (AD)- like effects of known and putative antidepressants. The FSL rat typically exhibits an AD-like effect in behavioral tests for AD-like activity following chronic (14 days) treatment, although some studies have found AD-like effects after fewer days of treatment. In other observations, exaggerated swim test immobility in the FSL rat has been found to have a maternal influence, as shown by cross-fostering studies and observations of maternal behavior; the implications of this finding are still to be determined. Ongoing or recently completed studies have been performed in the laboratories of Marko Diksic of Canada, Aleksander Mathé of Sweden, Gregers Wegener of Denmark, Brian Harvey of South Africa, Paul Pilowsky and Rod Irvine of Australia, and Gal Yadid of Israel. Jennifer Loftis of Portland, Oregon, and Lynette Daws of San Antonio, Texas, have been working with the FSL rats in the United States. A puzzling feature of the FSL rat is its sensitivity to multiple chemicals, and its greater sensitivity to a variety of drugs with different mechanisms of action. It has been recently shown that each of these drugs feeds through G protein-coupled receptors to potassium-gated channels. Thus, an abnormality in the potassium channel could underlie the depressed-like behavior of the FSL rats. © 2013 by The American Society for Pharmacology and Experimental Therapeutics.


Heckman J.J.,University of North Carolina at Chapel Hill | Heckman J.J.,Columbia University | Heckman J.J.,The Graduate Center, CUNY
Nuclear Physics B | Year: 2016

Motivated by the recently reported diphoton excess at 750 GeV observed by both CMS and ATLAS, we study string-based particle physics models which can accommodate this signal. Quite remarkably, although Grand Unified Theories in F-theory tend to impose tight restrictions on candidate extra sectors, the case of a probe D3-brane near an E-type Yukawa point naturally leads to a class of strongly coupled models capable of accommodating the observed signature. In these models, the visible sector is realized by intersecting 7-branes, and the 750 GeV resonance is a scalar modulus associated with motion of the D3-brane in the direction transverse to the Standard Model 7-branes. Integrating out heavy 3-7 string messenger states leads to dimension five operators for gluon fusion production and diphoton decays. Due to the unified structure of interactions, these models also predict that there should be additional decay channels to ZZ and Zγ. We also comment on models with distorted unification, where both the production mechanism and decay channels can differ. © 2016 The Author.


Grant A.M.,University of Pennsylvania | Gino F.,University of North Carolina at Chapel Hill
Journal of Personality and Social Psychology | Year: 2010

Although research has established that receiving expressions of gratitude increases prosocial behavior, little is known about the psychological mechanisms that mediate this effect. We propose that gratitude expressions can enhance prosocial behavior through both agentic and communal mechanisms, such that when helpers are thanked for their efforts, they experience stronger feelings of self-efficacy and social worth, which motivate them to engage in prosocial behavior. In Experiments 1 and 2, receiving a brief written expression of gratitude motivated helpers to assist both the beneficiary who expressed gratitude and a different beneficiary. These effects of gratitude expressions were mediated by perceptions of social worth and not by self-efficacy or affect. In Experiment 3, we constructively replicated these effects in a field experiment: A manager's gratitude expression increased the number of calls made by university fundraisers, which was mediated by social worth but not self-efficacy. In Experiment 4, a different measure of social worth mediated the effects of an interpersonal gratitude expression. Our results support the communal perspective rather than the agentic perspective: Gratitude expressions increase prosocial behavior by enabling individuals to feel socially valued. © 2010 American Psychological Association.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 224.54K | Year: 2014

DESCRIPTION (provided by applicant): For medical practices, a major challenge is managing the hundreds of telephone calls received daily, many of which are about new or worsening medical symptoms. Particularly difficult are calls from persons with little or no medical training about frail older persons living at home or in assisted living (AL) communities. Incoming calls are typically answered by a receptionist with little medical training, who takes basic information and passes the call to an office nurse,who resolves the call with occasional provider backup. Consistent, high-quality management and documentation of these telephone contacts is a formidable task for both medical offices and AL communities. Standard protocols and triage systems exist for obstetrics, pediatrics, and general adult medicine, but no geriatric-specific products exist, and integration of telephone information-gathering systems with electronic health records (EHRs) is rudimentary. Thus, a growing need exists in the healthcare m


Bray G.A.,Louisiana State University | Popkin B.M.,University of North Carolina at Chapel Hill
Diabetes Care | Year: 2014

Sugar-sweetened drinks have been associated with several health problems. In the point narrative as presented below, we provide our opinion and review of the data to date that we need to reconsider consumption of dietary sugar based on the growing concern of obesity and type 2 diabetes. In the counterpoint narrative following our contribution, Drs. Kahn and Sievenpiper provide a defense and suggest that dietary sugar is not the culprit. Data from the National Health and Nutrition Examination Survey and U.S. Department of Agriculture dietary surveys along with commercial Homescan data on household purchases were used to understand changes in sugar and fructose consumption. Meta-analyses and randomized clinical trials were used to evaluate outcomes of beverage and fructose intake. About 75% of all foods and beverages contain added sugar in a large array of forms. Consumption of soft drinks has increased fivefold since 1950. Meta-analyses suggest that consumption of sugar-sweetened beverages (SSBs) is related to the risk of diabetes, the metabolic syndrome, and cardiovascular disease. Drinking two 16-ounce SSBs per day for 6 months induced features of the metabolic syndrome and fatty liver. Randomized controlled trials in children and adults lasting 6 months to 2 years have shown that lowering the intake of soft drinks reduced weight gain. Recent studies suggest a gene-SSB potential relationship. Consumption of calorie-sweetened beverages has continued to increase and plays a role in the epidemic of obesity, the metabolic syndrome, and fatty liver disease. Reducing intake of soft drinks is associated with less weight gain. © 2014 by the American Diabetes Association.


Khakh B.S.,University of California at Los Angeles | McCarthy K.D.,University of North Carolina at Chapel Hill
Cold Spring Harbor Perspectives in Biology | Year: 2015

We provide an overview of recent progress on the study of astrocyte intracellular Ca2+ signaling. We consider the methods that have been used to monitor astrocyte Ca2+ signals, the various types of Ca2+ signals that have been discovered (waves, microdomains, and intrinsic fluctuations), the approaches used to broadly trigger and block Ca2+ signals, and, where possible, the proposed and demonstrated physiological roles for astrocyte Ca2+ signals within neuronal microcircuits. Although important progress has been made, we suggest that further detailed work is needed to explore the biophysics and molecular mechanisms of Ca2+ signaling within entire astrocytes, including their fine distal extensions, such as processes that interact spatially with neurons and blood vessels. Improved methods are also needed to mimic and block molecularly defined types of Ca2+ signals within genetically specified populations of astrocytes. Moreover, it will be essential to study astrocyte Ca2+ activity in vivo to distinguish between pharmacological and physiological activity, and to study Ca2+ activity in situ to rigorously explore mechanisms. Once methods to reliably measure, mimic, and block specific astrocyte Ca2+ signals with high temporal and spatial precision are available, researchers will be able to carefully explore the correlative and causative roles that Ca2+ signals may play in the functions of astrocytes, blood vessels, neurons, and microcircuits in the healthy and diseased brain. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.


Patent
Cornell University, Louisiana State University, University of North Carolina at Chapel Hill and Northeastern University | Date: 2014-02-10

The present invention relates to a device comprising a biomolecular processor. Each biomolecular processor has one or more bioreactor chambers defined by a solid substrate; a support structure within each bioreactor; a cleaving enzyme immobilized to the support structure and operatively positioned within the bioreactor chamber to cleave monomer or multimer units of a biopolymer molecule operatively engaged by the cleaving enzyme; and one or more time-of-flight channels formed in the solid substrate and fluidically coupled to said one or more bioreactor chambers. Each of the time-of-flight channels have two or more sensors including at least (i) a first sensor contacting the time-of-flight channel proximate to the input end of the channel and (ii) a second sensor contacting the time-of-flight channel proximate to the output end of channel. The present invention further relates to methods of sequencing and identifying biopolymer molecules using the device.


Patent
Roche Molecular Systems, University of North Carolina at Chapel Hill and Biofluidica Inc | Date: 2013-11-08

This invention provides methods and compositions for capturing circulating tumor cells (CTCs) as well as various divergent CTC phenotypes using seprase-specific affinity reagents. Methods of analyzing CTCs and assessing their metastatic potential in vivo and in vitro are also disclosed.


Patent
Sun Yat Sen University and University of North Carolina at Chapel Hill | Date: 2013-08-02

Disclosed are an N-substituted pyrazolo[3,4-d]pyrimidine ketone compound of formula (I), and a preparation process and use thereof as a phosphodiesterase IX (PDEIX) inhibitor: D- or L-configured CHCH_(3)CONHR, D- or L-configured CH_(2)CONHR, D- or L-configured CH_(2)CH_(2)CONHR; wherein R_(1 )is selected from hydrogen, chlorine, methoxy, methyl, trifluoromethyl, dimethoxy, methylenedioxy, and dichlorine, and R_(2 )is selected from hydrogen, methoxy, ethoxy, isopropoxy, methyl, dimethoxy, and 2-methyl-4-methoxy, and wherein R is p-methoxyphenyl.


Grant
Agency: National Science Foundation | Branch: | Program: STTR | Phase: Phase I | Award Amount: 225.00K | Year: 2013

This Small Business Technology Transfer Phase I project takes an innovative approach at tumor targeting by investigating an entirely novel tumor targeting platform that utilizes bone marrow derived, circulating tumor homing cells as natural vectors. Through screening of phage display peptide libraries we have identified high affinity peptide ligands that bind these cells with high specificity. These high affinity, high specificity peptide ligands and their applications for molecular imaging of tumor?s blood supply represent the innovation in this Phase I project. Radiolabeled peptide directed compounds will be synthersized and their potential to deliver molecular ?payloads? specifically to malignant vasculature in a mouse model of cancer will be characterized. The results from this development effort will provide proof-of-principle validation for a new targeting paradigm in which circulating tumor localizing cell populations can be exploited for highly transformative and innovative technology development for the benefit of cancer patients. The broader impact of this project and the commercialization of the molecular diagnostic tracer developed here will have important implications for furthering oncology care through personalized approaches: First, specific and sensitive imaging based on monitoring of homing of circulating cells to tumor tissue will be beneficial for tumor staging and re-staging. Second, in addition the outcomes of this development effort would provide more predictable information relevant to treatment that has been lacking so far. Close assessment of patient?s response to treatment by monitoring the presence or absence of circulating tumor homing cells would improve treatment outcomes and guide the development of personalized therapies. Third, especially promising clinical direction is to selectively deliver anti-angiogenic, and therapeutic compounds as anticancer strategies. Because endogenous cells are utilized as natural biologic vectors, the barriers to commercialization and clinical implementation of our innovative diagnostic tracer are much lower than for other emerging technologies.


Pickles R.J.,University of North Carolina at Chapel Hill | DeVincenzo J.P.,University of Memphis
Journal of Pathology | Year: 2015

Infants and young children with acute onset of wheezing and reduced respiratory airflows are often diagnosed with obstruction and inflammation of the small bronchiolar airways, ie bronchiolitis. The most common aetological agents causing bronchiolitis in young children are the respiratory viruses, and of the commonly encountered respiratory viruses, respiratory syncytial virus (RSV) has a propensity for causing bronchiolitis. Indeed, RSV bronchiolitis remains the major reason why previously healthy infants are admitted to hospital. Why RSV infection is such a predominant cause of bronchiolitis is the subject of this review. By reviewing the available histopathology of RSV bronchiolitis, both in humans and relevant animal models, we identify hallmark features of RSV infection of the distal airways and focus attention on the consequences of columnar cell cytopathology occurring in the bronchioles, which directly impacts the development of bronchiolar obstruction, inflammation and disease. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Heckman J.J.,University of North Carolina at Chapel Hill | Heckman J.J.,Jefferson Lab
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2015

M5-branes probing an ADE singularity lead to 6D SCFTs with (1, 0) supersymmetry. On the tensor branch, the M5-branes specify domain walls of a 7D Super Yang-Mills theory with gauge group G of ADE-type, thus providing conformal matter for a broad class of generalized quiver theories. Additionally, these theories have G×. G flavor symmetry, and a corresponding Higgs branch. In this Note we use the F-theory realization of these theories to calculate the scaling dimension of the operator parameterizing seven-brane recombination, i.e. motion of the stack of M5-branes off of the orbifold singularity. In all cases with an interacting fixed point, we find that this operator has scaling dimension at least six, and defines a marginal irrelevant deformation. © 2015.


Choi J.,Rutgers University | MacArthur A.H.R.,U.S. Naval Academy | Brookhart M.,University of North Carolina at Chapel Hill | Goldman A.S.,Rutgers University
Chemical Reviews | Year: 2011

Studies conducted in the field of dehydrogenation and related reactions catalyzed by iridium pincer complexes are compiled. Koridze et al. reported that ferrocene and ruthenocene-based iridium pincer complexes showing excellent catalytic activity for COA/TBE transfer dehydrogenation. In 2006, Goldman, Brookhart, and co-workers reported alkane metathesis by tandem alkane dehydrogenation and olefin metathesis using combinations of an iridium pincer complex and the Schrock catalyst. Kaska and Jensen reported the dehydrogenation of ethylbenzene and tetrahydrofuran and proposed that interaction between the catalyst and arene or oxygen groups inhibited the catalysis. In 2006, ammonia-borane dehydrogenation by a well-defined molecular complex was reported by Goldberg and Heinekey, and it was considered that alkane dehydrogenation catalysts might also effect the dehydrogenation of ammonia-borane.


Li K.,University of Memphis | Lemon S.M.,University of North Carolina at Chapel Hill
Seminars in Immunopathology | Year: 2013

Hepatitis C virus (HCV) is a major causative agent of chronic hepatitis and hepatocellular carcinoma worldwide and thus poses a significant public health threat. A hallmark of HCV infection is the extraordinary ability of the virus to persist in a majority of infected people. Innate immune responses represent the front line of defense of the human body against HCV immediately after infection. They also play a crucial role in orchestrating subsequent HCV-specific adaptive immunity that is pivotal for viral clearance. Accumulating evidence suggests that the host has evolved multifaceted innate immune mechanisms to sense HCV infection and elicit defense responses, while HCV has developed elaborate strategies to circumvent many of these. Defining the interplay of HCV with host innate immunity reveals mechanistic insights into hepatitis C pathogenesis and informs approaches to therapy. In this review, we summarize recent advances in understanding innate immune responses to HCV infection, focusing on induction and effector mechanisms of the interferon antiviral response as well as the evasion strategies of HCV. © 2012 Springer-Verlag.


Haibach M.C.,Rutgers University | Kundu S.,University of North Carolina at Chapel Hill | Brookhart M.,University of North Carolina at Chapel Hill | Goldman A.S.,Rutgers University
Accounts of Chemical Research | Year: 2012

Methods for the conversion of both renewable and non-petroleum fossil carbon sources to transportation fuels that are both efficient and economically viable could greatly enhance global security and prosperity. Currently, the major route to convert natural gas and coal to liquids is Fischer-Tropsch catalysis, which is potentially applicable to any source of synthesis gas including biomass and nonconventional fossil carbon sources. The major desired products of Fischer-Tropsch catalysis are n-alkanes that contain 9-19 carbons; they comprise a clean-burning and high combustion quality diesel, jet, and marine fuel. However, Fischer-Tropsch catalysis also results in significant yields of the much less valuable C 3 to C 8 n-alkanes; these are also present in large quantities in oil and gas reserves (natural gas liquids) and can be produced from the direct reduction of carbohydrates. Therefore, methods that could disproportionate medium-weight (C 3-C 8) n-alkanes into heavy and light n-alkanes offer great potential value as global demand for fuel increases and petroleum reserves decrease. This Account describes systems that we have developed for alkane metathesis based on the tandem operation of catalysts for alkane dehydrogenation and olefin metathesis. As dehydrogenation catalysts, we used pincer-ligated iridium complexes, and we initially investigated Schrock-type Mo or W alkylidene complexes as olefin metathesis catalysts. The interoperability of the catalysts typically represents a major challenge in tandem catalysis. In our systems, the rate of alkane dehydrogenation generally limits the overall reaction rate, whereas the lifetime of the alkylidene complexes at the relatively high temperatures required to obtain practical dehydrogenation rates (ca. 125-200 °C) limits the total turnover numbers. Accordingly, we have focused on the development and use of more active dehydrogenation catalysts and more stable olefinmetathesis catalysts. We have used thermally stable solid metal oxides as the olefin-metathesis catalysts. Both the pincer complexes and the alkylidene complexes have been supported on alumina via adsorption through basic para-substituents. This process does not significantly affect catalyst activity, and in some cases it increases both the catalyst lifetime and the compatibility of the co-catalysts. These molecular catalysts are the first systems that effect alkane metathesis with molecular-weight selectivity, particularly for the conversion of C n n-alkanes to C 2n-2n-alkanes plus ethane. This molecular-weight selectivity offers a critical advantage over the few previously reported alkane metathesis systems. We have studied the factors that determine molecular-weight selectivity in depth, including the isomerization of the olefinic intermediates and the regioselectivity of the pincer-iridium catalyst for dehydrogenation at the terminal position of the n-alkane. Our continuing work centers on the development of co-catalysts with improved interoperability, particularly olefin-metathesis catalysts that are more robust at high temperature and dehydrogenation catalysts that are more active at low temperature. We are also designing dehydrogenation catalysts based on metals other than iridium. Our ongoing mechanistic studies are focused on the apparently complex combination of factors that determine molecular-weight selectivity. © 2012 American Chemical Society.


Patent
University of North Carolina at Chapel Hill and The University Of Texas System | Date: 2014-11-24

Contrast agents and methods for use in geological applications are provided. Contrast agents can be a nanopolymorph material, such as titania nanotubes, and have a low-frequency dielectric permittivity. Methods of identifying one or more subterranean features during geological exploration are provided. Methods of identifying a ganglion of bypassed oil are provided. Methods of illuminating subterranean fractures in hydraulic fracturing are provided.


Patent
Phoenixsongs Biologicals and University of North Carolina at Chapel Hill | Date: 2015-10-13

The present invention provides biomatrix scaffolds for industrial scale dispersal.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 1.40M | Year: 2012

DESCRIPTION (provided by applicant): The human inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, affect over one million Americans and significant unmet medical needs still exist. Activation of NF??B transcription factors are central events in the initiation and perpetuation of chronic inflammation in IBD. TheraLogics, Inc., have been at the forefront of NF??B research and hold intellectual property pertaining to novel NF??B inhibitor peptides including TLX1423. TLX1423 is a peptidecomprised of a 8 lysine (8K) protein transduction domain (PTD) with an I?B kinase (IKK) inhibitory sequence, NF??B essential modulator (NEMO) binding domain (NBD). Compared to other NF??B inhibitors, TLX1423 has the advantages of inhibiting activatedNF??B, a hallmark of chronic inflammation, but not inhibiting basal NF??B activity, involved in fundamental cellular processes thus correlating with toxicity. During phase 1, we achieved important milestones in the development of TLX1423 as a therapy for IBD and published these findings in the Journal of Immunology. We demonstrated transduction of TLX1423 into cells and tissues. In-vivo, TLX1423 inhibited LPS-activated NF??B in the ileum, but did not inhibit basal NF??B in Peyer's patches. IL-10-/- mice treated systemically with TLX1423 demonstrated amelioration of established colitis and decreased NF??B activation in the lamina propria. In phase 1, we also demonstrated that intrarectal administration of TLX1423 results in amelioration of intestinal inflammation in two experimental IBD models. The ideal therapeutic agent to treat IBD would be administered by mouth. However, drug delivery to the inflamed intestine remains a challenge for two main reasons: 1) lack of highly effective immunomodulatory agents that can be delivered locally and inhibit their targets in intestinal immune cells and, 2) lack of vehicles to carry these agents to the site of inflammation with minimal degradation in the GI tract. The multidisciplinary team assembled for this phase 2 proposal has developed innovative solutions to these hurdles. This would be an important advancement to minimize toxicity, increase patient compliance, and improve quality of life. To address these challenges, we have developed microemulsion (ME)- based delivery systems suitable for local administration of TLX1423, and via enteric release strategies, target the peptide to inflamed regions of the GI tract. We show preliminary data that PTD peptides in water-in-oil (w/o) MEs are efficiently delivered to the largeintestine in mice as compared to free PTD peptides. TheraLogics has enlisted CMC, regulatory and clinical consultants to translate results of this phase 2 program into the next phases, including GMP manufacturing, GLP safety/toxicity studies, and an IND submission. PUBLIC HEALTH RELEVANCE: This is an STTR application representing an industry-academic collaboration between TheraLogics, Inc., the University of North Carolina at Chapel Hill, and the North Carolina State School of Veterinary Medicine.The applicant organization is TheraLogics, Inc., a small North Carolina based biotechnology company. The Principal Investigator on this application is Scott E. Plevy in the University of North Carolina School of Medicine. The purpose of this application is to develop a novel NF??B inhibitor for the treatment of inflammatory bowel disease. The investigators have already been successful in demonstrating efficacy of the NF??B inhibitor in experimental models of colitis. This application will further develop this inhibitor for oral delivery and further test this molecule in small and lrge animals. It is our hope that the work performed in this application will lead to clinical development in humans in the next phase.


Patent
University of North Carolina at Chapel Hill and Anglefix Technology LLC | Date: 2014-10-15

A fastening apparatus includes a fastener and a fastener receiving member, the apparatus enabling the fastener to be affixed to the fastener receiving member at a variable insertion angle selected by the user and providing an anti-unscrewing feature. The fastener includes an elongate section and an adjoining head section having a slot therein. The fastener receiving member includes one or more apertures having a contact region through which one or more corresponding fasteners can be inserted. The contact region includes a matrix of protrusions having a density and strength sufficient to render contact region tappable by the thread of the head section of the fastener. The thread on the head section is driven into the contact region at the selected insertion angle. As a result, the protrusions project into the at least one slot preventing the fastener from backing out from fastener receiving member. A fastener driver is also disclosed.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 656.97K | Year: 2012

DESCRIPTION (provided by applicant): The mu-opioid receptor (MOR) is the primary target for opioid analgesics. While opioids are the most frequently used and effective analgesics for the treatment of moderate to severe clinical pain, their prolonged use leads to reduced efficacy and a number of adverse side effects, including post dosing-induced hyperalgesia and analgesic tolerance. MOR induces analgesia through several mechanisms including the inhibition of second messenger pathways and modulation of ion channel activity. Nevertheless, the opposite, opioid induced cellular excitation, has also been demonstrated and proposed to mediate reductions in efficacy, tolerance, and opioid-induced hyperalgesia following the exposure to opioids. While an array of mechanisms has been advanced that contribute to these use-dependence changes in MOR-mediated effects, we have recently identified a novel mechanism underlying the shift in MOR signaling: a MOR splice variant encoding a functional 6 transmembrane (6TM) receptor. This 6TM isoform was identified in a study designed to determine the genetic basis for variability in sensitivity to exogenous opiates. Importantly, morphine exposure to cells overexpressing the 6TM receptor isoform leads to excitatory cellular effects rather than the classic inhibitory effects that are produced by stimulating the canonical 7TM MOR isoform. The discovery of this new alternative 6TM isoform, which evokes responses that oppose the biological effects of the major 7TM isoform, provides a unique opportunity to identify pharmacological probes that will further our understanding of the mechanisms that mediate the pharmacodynamic effects of opioids and will enable the future development of new opioid compounds that show 7TM agonist and/or 6TM antagonist properties providing high analgesic efficacy with a diminished ability to produce post dosing-induced hyperalgesia, analgesic tolerance, and unwanted physiological side effects. To take maximal advantage of this opportunity, an interdisciplinary investigative team with unique, but complementary, areas of expertise has been assembled to develop, validate and characterize the in silico models of the major 7TM and alternative 6TM receptor isoforms can be used to identity putative isoform selective compounds. The long-term goal of this effort is to develop novel opioids that evoke high potency analgesia without deleterious short- or long-term consequences. PUBLIC HEALTH RELEVANCE: While opioids are the most frequently used and effective analgesicsfor the treatment of moderate to severe clinical pain, their prolonged use leads to a number of treatment limiting side-effects in a large percentage of patients. An experienced multidisciplinary investigative team proposes a set of studies that have derived from new data on the molecular and signaling basis of opioid receptor pharmacology and associated side-effects. These studies will build in silico models of the human 5-opioid receptor isoforms whose activities differentially contribute to the clinicalefficacy of opioids and allow identification of novel and potentially a new class of opioid compounds that will show high analgesic properties with a diminished ability to produce opioid-induced hyperalgesia, analgesic tolerance, and unwanted physiologicalside effects.

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