Farmington, CT, United States

University of Connecticut Health Center
Farmington, CT, United States

UConn Health is the branch of the University of Connecticut that oversees clinical care, advanced biomedical research, and premier academics in medicine. The main branch is located in Farmington, in the US state of Connecticut. It includes a teaching hospital , the UConn School of Medicine, School of Dental Medicine, and Graduate School. Other smaller branches of UConn Health exist in Storrs and Canton. The university owns and operates many smaller clinics around the state that contain UConn Medical Group, UConn Health Partners, University Dentists and research facilities.UConn Health Center has about 5,000 employees, and is closely linked with the University of Connecticut's main campus in Storrs through several cross-campus academic projects. UConn Health Center is part of a plan introduced by Connecticut Governor Dannel P. Malloy, called "Bioscience Connecticut," and approved by the Connecticut General Assembly in 2011, to stimulate the economy in the state of Connecticut. Wikipedia.

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University of Connecticut Health Center | Date: 2016-05-16

The present invention relates to methods of improving a treatment outcome comprising administering a heat shock protein (HSP) preparation or an -2-macroglobulin (2M) preparation with a non-vaccine treatment modality. In particular, an HSP preparation or an 2M preparation is administered in conjunction with a non-vaccine treatment modality for the treatment of cancer or infectious diseases. In the practice of the invention, a preparation comprising HSPs such as but not limited to, hsp70, hsp90 and gp96 alone or in combination with each other, noncovalently or covalently bound to antigenic molecules or 2M, noncovalently or covalently bound to antigenic molecules is administered in conjunction with a non-vaccine treatment modality.

Torti S.V.,University of Connecticut Health Center
Advanced Drug Delivery Reviews | Year: 2013

Thermal tumor ablation therapies are being developed with a variety of nanomaterials, including single- and multiwalled carbon nanotubes. Carbon nanotubes (CNTs) have attracted interest due to their potential for simultaneous imaging and therapy. In this review, we highlight in vivo applications of carbon nanotube-mediated thermal therapy (CNMTT) and examine the rationale for use of this treatment in recurrent tumors or those resistant to conventional cancer therapies. Additionally, we discuss strategies to localize and enhance the cancer selectivity of this treatment and briefly examine issues relating the toxicity and long term fate of CNTs. © 2013 Elsevier B.V.

Sheridan B.S.,University of Connecticut Health Center | Lefrancois L.,University of Connecticut Health Center
Nature Immunology | Year: 2011

After infection, most antigen-specific memory T cells reside in nonlymphoid tissues. Tissue-specific programming during priming leads to directed migration of T cells to the appropriate tissue, which promotes the development of tissue-resident memory in organs such as intestinal mucosa and skin. Mechanisms that regulate the retention of tissue-resident memory T cells include transforming growth factor-2 (TGF-2)-mediated induction of the E-cadherin receptor CD103 and downregulation of the chemokine receptor CCR7. These pathways enhance protection in internal organs, such as the nervous system, and in the barrier tissues-"the mucosa and skin. Memory T cells that reside at these surfaces provide a first line of defense against subsequent infection, and defining the factors that regulate their development is critical to understanding organ-based immunity. © 2011 Nature America, Inc. All rights reserved.

Nilsen T.W.,Case Western Reserve University | Graveley B.R.,University of Connecticut Health Center
Nature | Year: 2010

The collection of components required to carry out the intricate processes involved in generating and maintaining a living, breathing and, sometimes, thinking organism is staggeringly complex. Where do all of the parts come from? Early estimates stated that about 100,000 genes would be required to make up a mammal; however, the actual number is less than one-quarter of that, barely four times the number of genes in budding yeast. It is now clear that the 'missing' information is in large part provided by alternative splicing, the process by which multiple different functional messenger RNAs, and therefore proteins, can be synthesized from a single gene. © 2010 Macmillan Publishers Limited. All rights reserved.

Weller S.K.,University of Connecticut Health Center
Cold Spring Harbor perspectives in biology | Year: 2012

Herpes simplex virus (HSV) encodes seven proteins necessary for viral DNA synthesis-UL9 (origin-binding protein), ICP8 (single-strand DNA [ssDNA]-binding protein), UL30/UL42 (polymerase), and UL5/UL8/UL52 (helicase/primase). It is our intention to provide an up-to-date analysis of our understanding of the structures of these replication proteins and how they function during HSV replication. The potential roles of host repair and recombination proteins will also be discussed.

Torti S.V.,Microbial and Structural Biology | Torti F.M.,University of Connecticut Health Center
Nature Reviews Cancer | Year: 2013

Iron is an essential nutrient that facilitates cell proliferation and growth. However, iron also has the capacity to engage in redox cycling and free radical formation. Therefore, iron can contribute to both tumour initiation and tumour growth; recent work has also shown that iron has a role in the tumour microenvironment and in metastasis. Pathways of iron acquisition, efflux, storage and regulation are all perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumour cell survival. Signalling through hypoxia-inducible factor (HIF) and WNT pathways may contribute to altered iron metabolism in cancer. Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy. © 2013 Macmillan Publishers Limited. All rights reserved.

Hussain N.,University of Connecticut Health Center
Antioxidants and Redox Signaling | Year: 2012

Significance: Epigenetic modifications are key processes in understanding normal human development and are largely responsible for the myriad cell and tissue types that originate from a single-celled fertilized ovum. The three most common processes involved in bringing about epigenetic changes are DNA methylation, histone modification, and miRNA effects. There are critical periods in the development of the zygote, the embryo, and the fetus where in the organism is most susceptible to epigenetic influences because of normal demethylation and de novo methylation processes that occur in the womb. Recent Advances: A number of epigenetic modifications of normal growth patterns have been recognized, leading to altered development and disease states in the mammalian fetus and infant. 'Fetal programming' due to these epigenetic changes has been implicated in pathogenesis of adult-onset disease such as hypertension, diabetes, and cardiovascular disease. There may also be transgenerational effects of such epigenetic modifications. Critical Issues: The impact of environmental agents and endogenous factors such as stress at critical periods of infant development has immediate, life-long and even multi-generational effects. Both the timing and the degree of insult may be important. Understanding these influences may help prevent onset of disease and promote normal growth. Future Directions: Use of one-carbon metabolism modifying agents such as folic acid during critical periods of epigenetic modulation may have significant clinical impact. Their use as therapeutic agents in targeted epigenetic modulation of genes may be the new frontier for clinical therapeutics. © 2012 Mary Ann Liebert, Inc.

Agency: NSF | Branch: Continuing grant | Program: | Phase: Genetic Mechanisms | Award Amount: 218.00K | Year: 2016

This project aims to elucidate tightly controlled mechanisms that allow eukaryotic cells to faithfully reproduce their genetic material despite the presence of DNA damage. DNA lesions can block replication, triggering a cascade of events leading to cell death. To prevent this, cells utilize translesion synthesis (TLS) DNA polymerases that can copy over the DNA lesions while temporarily leaving them unrepaired. These TLS enzymes are central to cell survival after DNA damage; however, they are also error-prone and often introduce mutations in genomic DNA. The project will employ an interdisciplinary approach that combines structural biology, biochemical methods and in vivo assays to decipher key protein-protein interactions (PPIs) underlying mutagenic TLS in a yeast model system. This research will advance our understanding of the structural organization of the multi-protein TLS complexes and also provide new insights into mechanistic questions about TLS: How do mutagenic TLS enzymes gain access to DNA replication forks? How do active multi-polymerase complexes assemble? What molecular events drive TLS DNA polymerase switching? These questions are central to our understanding of events leading to mutagenesis in eukaryotes and the ability of cells to cope with DNA damage and faithfully transfer genetic information from one generation to the next. This project creates a solid platform for integration of research and education at multiple levels, from advanced post-PhD training to K-12 education. The project will provide plentiful material for graduate and undergraduate teaching, including advanced training courses such as the Connecticut NMR Workshop, laboratory projects for graduate students, and mini-projects for the diverse undergraduate students from the Undergraduate Summer Research Internship program. Finally, it will also engage students from the nearby Farmington High School in real world scientific research under the umbrella of the Cutting Edge Bioresearch Internship program.

In S. cerevisiae, replicative bypass of most DNA lesions requires the coordinated action of TLS polymerases Rev1, pol eta and pol zeta that replace replicative polymerases at replication forks stalled by DNA damage or fill damage-containing single-stranded DNA gaps left after replication. This process is initiated by mono-ubiquitination of the processivity factor PCNA, which plays a key role in the assembly of the multi-polymerase TLS complex at DNA damage sites. The mechanism by which this TLS complex, often called the Rev1/pol zeta mutasome, is assembled on ubiquitinated PCNA is poorly understood. Important questions remain unanswered about how TLS enzymes gain access to sites of DNA damage and how DNA polymerases switch during TLS. The main goal of this project is to understand the mechanisms by which the TLS mutasome achieves efficient lesion bypass by analyzing its organization at a structural level. Our central hypothesis is that mutasome activity is regulated by protein-protein interactions (PPIs) mediated by accessory domains and regulatory subunits of the TLS DNA polymerases. We will test this hypothesis by using a structural analysis to precisely map PPIs that influence the assembly of the S. cerevisiae Rev1/pol zeta mutasome, combined with in vivo assays to probe the significance of these PPIs for mutagenic TLS. To date, the structure and PPIs of accessory modules of yeast TLS enzymes remain largely uncharacterized. To gain insights into the structural organization and regulation of the yeast TLS machinery, we will undertake the following specific aims. In Aim 1, we will examine key PPIs that control the Rev1/pol zeta mutasome interactions with the sliding clamp PCNA. In Aim 2, we will determine structures and probe PPIs of the essential accessory modules that mediate assembly of the Rev1/pol zeta complex. In Aim 3, we will explore additional PPIs that stabilize multi-subunit Rev1/pol zeta assembly. The project will provide new insights into how individual components of the TLS mutasome work together to achieve efficient lesion bypass.

The project is funded jointly by the Genetic Mechanisms Cluster and the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences.

Agency: NSF | Branch: Standard Grant | Program: | Phase: RSCH EXPER FOR UNDERGRAD SITES | Award Amount: 374.98K | Year: 2015

Many biological processes that underlie human health, an abundant and high quality food supply, a healthy and sustainable environment, and a renewable energy supply are complex, with multiple intertwined feedback loops. Systems biology uses mathematics and mathematical models as the key enabling technology to capture this complexity in predictive computer models that allow the efficient design of control strategies, such as the development of new drugs for a variety of human, animal, and plant diseases. There is considerable need for mathematical scientists trained in the development and application of mathematical algorithms for systems biology, and this project focuses on meeting this need. The program takes advantage of a unique research environment that brings together several ongoing programs to develop and implement mathematical algorithms for modeling, simulation, and control of molecular networks. It provides a 10-week, in-residence, intensive summer research program for U.S. citizen or permanent resident undergraduate students from around the United States and Puerto Rico. It will provide participants with a broad view of available career opportunities for mathematical scientists in academia, industry, and government. Participants will have the opportunity to expand their professional network of peers and mentors. The award is supported by the Division of Mathematical Sciences (DMS) in the Directorate for Mathematical and Physical Sciences (MPS) and the Division of Biological Infrastructure (DBI) in the Directorate for Biological Sciences (BIO).

Modeling and simulation is a key technology for systems biology. The focus is on biological systems that might be organized into gene regulatory, signaling, or metabolic networks, maybe linked with spatial processes, such as translocation of molecules across cellular compartments. Various intertwined feedback and feedforward loops might be involved in the regulation of the system, linking the molecular with the systemic level. Mathematical models of various kinds are indispensable tools in the effort to understand these systems. There is a clear need for mathematical scientists whose expertise can address these complexities in innovative and rigorous ways. Career opportunities for mathematical scientists with expertise in the biosciences are plentiful in both academics and in industry, in particular in the health care field.

Agency: NSF | Branch: Standard Grant | Program: | Phase: Molecular Biophysics | Award Amount: 599.00K | Year: 2016

Title: Activation and specificity of USP7: uncovering the molecular mechanisms.

This multidisciplinary project will provide a fundamental understanding of the mechanism of action of a new class of enzymes. It focuses on one member of this class, the human enzyme USP7, that plays a central role in fundamental cellular processes such as DNA regulation, stress response and protein stability control. The aim of this project is to understand how the activity of USP7 is regulated and how it recognizes its diverse targets. To fill a critical gap in knowledge of USP7 function, an interdisciplinary approach will be employed that combines solution Nuclear Magnetic Resonance (NMR) spectroscopy, cryo-Electron Microscopy, Small-Angle X-ray Scattering (SAXS), a variety of biophysical and biochemical methods, and a range of in vitro and in vivo assays. This project will create a platform for teaching, training and learning, including outreach to underrepresented minorities to promote understanding of basic science. This project will also promote teaching and training in the K-12 environment by creating several short-term educational and training opportunities.

The goal of this project is to elucidate the molecular mechanisms of activation and substrate specificity of the deubiquitinating enzyme USP7, which rescues a number of diverse cellular and viral proteins from proteasomal degradation. Its substrates include a number of transcription factors, E3 ubiquitin ligases and epigenetic modifiers. USP7 exemplifies a newly recognized subgroup of deubiquitinating enzymes that is characterized by the presence of multiple ubiquitin-like domains (UBLs). These UBL domains are not catalytically active, but can greatly influence the activity of the enzyme by a yet unknown mechanism. The mechanisms of USP7 activation will be addressed by determining the arrangement of individual USP7 domains within the full-length enzyme. The molecular basis of USP7 specificity towards its substrates will be addressed by identifying and mapping distinct sites on C-USP7 responsible for recognition of two transcription factors, p53 and FOX(O)4. An array biophysical and spectroscopic methods will be employed in vitro and in vivo experiments. This project is supported by the Molecular Biophysics Cluster of the Molecular and Cellular Biosciences Division in the Directorate for Biological Sciences.

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