San Diego, CA, United States

Burnham Institute for Medical Research

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San Diego, CA, United States

The Sanford-Burnham Medical Research Institute, previously Burnham Institute for Medical Research, is a non-profit medical research institute with locations in La Jolla, California, Orlando, Florida, and Santa Barbara, California. There are more than 850 scientists at Sanford-Burnham; they work on the fundamental molecular causes of various diseases, with research including topics such as cancer, neuroscience, stem cell research, diabetes and obesity.Research at Sanford-Burnham is supported by funding from National Institutes of Health, National Cancer Institute, and Juvenile Diabetes Research Foundation among others, and partnerships with pharmaceutical companies such as Johnson & Johnson Pharmaceutical Research and Development. In 2008, Sanford-Burnham was awarded a $97.9 million grant by NIH to establish a high-throughput screening screening center. Wikipedia.

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News Article | May 5, 2017
Site: www.eurekalert.org

(New York - May 5, 2017) - Much is known about flu viruses, but little is understood about how they reproduce inside human host cells, spreading infection. Now, a research team headed by investigators from the Icahn School of Medicine at Mount Sinai is the first to identify a mechanism by which influenza A, a family of pathogens that includes the most deadly strains of flu worldwide, hijacks cellular machinery to replicate. The study findings, published online today in Cell, also identifies a link between congenital defects in that machinery -- the RNA exosome -- and the neurodegeneration that results in people who have that rare mutation. It was by studying the cells of patients with an RNA exosome mutation, which were contributed by six collaborating medical centers, that the investigators were able to understand how influenza A hijacks the RNA exosome inside a cell's nucleus for its own purposes. "This study shows how we can discover genes linked to disease -- in this case, neurodegeneration -- by looking at the natural symbiosis between a host and a pathogen," says the study's senior investigator, Ivan Marazzi, PhD, an assistant professor in the Department of Microbiology at the Icahn School of Medicine at Mount Sinai. Influenza A is responsible in part not only for seasonal flus but also pandemics such as H1N1 and other flus that cross from mammals (such as swine) or birds into humans. "We are all a result of co-evolution with viruses, bacteria, and other microbes, but when this process is interrupted, which we call the broken symmetry hypothesis, disease can result," Dr. Marazzi says. The genes affected in these rare cases of neurodegeneration caused by a congenital RNA exosome mutation may offer future insight into more common brain disorders, such as Alzheimer's and Parkinson's diseases, he added. In the case of Influenza A, the loss of RNA exosome activity severely compromises viral infectivity, but also manifests in human neurodegeneration suggesting that viruses target essential proteins implicated in rare disease in order to ensure continual adaptation. Influenza A is an RNA virus, meaning that it reproduces itself inside the nucleus. Most viruses replicate in a cell's cytoplasm, outside the nucleus. The researchers found that once inside the nucleus, influenza A hijacks the RNA exosome, an essential protein complex that degrades RNA as a way to regulate gene expression. The flu pathogen needs extra RNA to start the replication process so it steals these molecules from the hijacked exosome, Dr. Marazzi says. "Viruses have a very intelligent way of not messing too much with our own biology," he says. "It makes use of our by-products, so rather than allowing the exosome to chew up and degrade excess RNA, it tags the exosome and steals the RNA it needs before it is destroyed. "Without an RNA exosome, a virus cannot grow, so the agreement between the virus and host is that it is ok for the virus to use some of the host RNA because the host has other ways to suppress the virus that is replicated," says the study's lead author, Alex Rialdi, MPH, a graduate assistant in Dr. Marazzi's laboratory. Co-authors include investigators from the University of California-San Francisco, Columbia University, Regeneron Pharmaceuticals and Regeneron Genetics Center, Burnham Institute for Medical Research, and the University of California-Los Angeles. The study was supported by NIH grants 2RO1AI099195 and DP2 2OD008651 (U.B.), and partially supported by HHSN272201400008C - Center for Research on Influenza Pathogenesis (CRIP) a NIAID-funded Center of Excellence for Influenza Research and Surveillance (A.G.S, H.v.B., R.A., and I.M.). Other support includes the Department of Defense W911NF-14-1-0353 (to I.M.) NIH grant 1R56AI114770-01A1 (to I. M.), NIH grant 1R01AN3663134 (I.M. and H.v.B), and NIH grant U19AI106754 FLUOMICS (I.M., R.A., S.C., N.K., A.G.S.). The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services -- from community-based facilities to tertiary and quaternary care. The System includes approximately 7,100 primary and specialty care physicians; 12 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked among the highest in the nation in National Institutes of Health funding per investigator. The Mount Sinai Hospital is in the "Honor Roll" of best hospitals in America, ranked No. 15 nationally in the 2016-2017 "Best Hospitals" issue of U.S. News & World Report. The Mount Sinai Hospital is also ranked as one of the nation's top 20 hospitals in Geriatrics, Gastroenterology/GI Surgery, Cardiology/Heart Surgery, Diabetes/Endocrinology, Nephrology, Neurology/Neurosurgery, and Ear, Nose & Throat, and is in the top 50 in four other specialties. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 10 nationally for Ophthalmology, while Mount Sinai Beth Israel, Mount Sinai St. Luke's, and Mount Sinai West are ranked regionally. Mount Sinai's Kravis Children's Hospital is ranked in seven out of ten pediatric specialties by U.S. News & World Report in "Best Children's Hospitals." For more information, visit http://www. , or find Mount Sinai on Facebook, Twitter and YouTube.


McCarroll J.,University of Massachusetts Medical School | McCarroll J.,Childrens Cancer Institute Australia for Medical Research | Baigude H.,University of Massachusetts Medical School | Baigude H.,Burnham Institute for Medical Research | And 4 more authors.
Bioconjugate Chemistry | Year: 2010

Single-walled carbon nanotubes (SWNT) have unique electronic, mechanical, and structural properties as well as chemical stability that make them ideal nanomaterials for applications in materials science and medicine. Here, we report the design and creation of a novel strategy for functionalizing SWNT to systemically silence a target gene in mice by delivering siRNA at doses of <1 mg/kg. SWNT were functionalized with lipids and natural amino acid-based dendrimers (TOT) and complexed to siRNA. Our model study of the silencing efficiency of the TOT-siRNA complex showed that, in mice injected at 0.96 mg/kg, an endogenous gene for apoliproprotein B (ApoB) was silenced in liver, plasma levels of ApoB decreased, and total plasma cholesterol decreased. TOT-siRNA treatment was nontoxic and did not induce an immune response. Most (80%) of the RNA trigger molecules assembled with TOT were cleared from the body 48 h after injection, suggesting that the nanotubes did not cause siRNA aggregation or inhibit biodegradation and drug clearance in vivo. These results provide the first evidence that nanotubes can be functionalized with lipids and amino acids to systemically deliver siRNA. This new technology not only can be used for systemic RNAi, but may also be used to deliver other drugs in vivo. © 2010 American Chemical Society.


Liu A.G.,Louisiana State University | Smith S.R.,Burnham Institute for Medical Research | Fujioka K.,Scripps Research Institute | Greenway F.L.,Louisiana State University
Obesity | Year: 2013

Objective To evaluate the effects of combination caffeine/ephedrine and leptin A-200 on visceral fat mass and weight loss over 24 weeks. Design and Methods In this randomized, double-blind, parallel-arm trial, 90 obese subjects received one of the three treatments for 24 weeks: 200 mg caffeine/20 mg ephedrine t.i.d. (CE), leptin A-200 (recombinant methionyl human Fc-leptin, 20 mg q.d.) (L), or combination leptin A-200 and caffeine/ephedrine (LCE). Outcomes included change in weight, visceral fat mass by computed tomography, lean mass and fat mass by dual energy X-ray absorptiometry. Results Groups treated with CE and LCE lost significant amounts of weight (-5.9 ± 1.2% and -6.5 ± 1.1%, P < 0.05) and whole body fat mass (-9.6 ± 2.4% and -12.4 ± 2.3%, P < 0.05) compared to leptin only group. Only treatment with LCE significantly reduced visceral fat mass (-11.0 ± 3.3%, P < 0.05). There were no differences in lean mass between treatment groups. Conclusions Our study provides evidence that CE is a modestly effective weight loss agent and produces significant reductions in fat mass. Leptin A-200 was not effective in producing weight loss and did not have any significant additive or synergistic actions when combined with CE. Copyright © 2013 The Obesity Society.


News Article | February 21, 2017
Site: www.prweb.com

The medical potential of stem cells is both extensive and astounding, and there are exciting prospects for their use, in multiple areas of medicine, due to their differentiating characteristics. Stem cells are unique as the have the potential to renew themselves through cellular division, and they have the ability to be induced to become tissue or organic-specific cells with special functions. Stem cell therapy in the form of bone marrow transplantation has already been utilised for decades, however research is now heavily focussed on alternative ways in which stem cells can be utilized, and they are now being consideration for applications including; in combination with gene therapy, for the treatment of autoimmune diseases, to remove unwanted cancer cells, and for use on scaffolds, with the capability of forming three-dimensional structures. Although the possibilities within regenerative medicine are endless; the associated challenges are still a hindering factor. The properties of stem cells are still incompletely understood, and how to successfully control their differentiation is often unclear, meaning that growing stem cells in conditions suitable for clinical use, remains a challenge and there is a fear that their ability to proliferate could lead to cancer following transplantation. The role of antibodies in stem cell research The characterisation of stem cells is vital. The routine process of validating starting cell populations should be simple, quick and reliable, to ensure accurate and consistent results. Transcription factors are essential for the regulation of gene expression, and are found in all living organisms; binding to either enhancer or promoter regions of DNA adjacent to the genes that they regulate. Within embryonic stem cells (ESC’s), the primary signalling pathways responsible for maintaining pluripotency and self-renewal cause the expression and activation of three key transcription factors; OCT-4, SOX2 and NANOG. The transcription factors expressed vary between different cell types; therefore, they can be used to isolate or identify differentiated versus non-differentiated cells. Antibodies are a vital tool to facilitate stem cell research, as they recognise certain markers, and also work against stem cell biomarkers to make them appropriate for bio imaging, immunofluorescence microscopy, multiplex protein assays, ELISA and Western blot analysis. When choosing a suitable antibody, it is important to consider multiple aspects of your experiment, including the nature of the sample, which determines which antibody is most appropriate, and which region of the protein that you wish to detect along with how the sample will be processed. The importance of choosing the most appropriate antibodies and the associated challenges As there are millions of antibodies available, and in most cases there is often more than one antibody available for each target, the challenge is being able to narrow down the choices on offer. Choosing the most appropriate antibody is essential; however one of the main challenges is antibody validation which is directly related to data irreproducibility. Out of 53 landmark studies in oncology and haematology, only 6 (11%) could be replicated. When researchers are choosing which antibody to consider for their research, One World Lab can offer the solution. Users can purchase antibodies in test size aliquots, meaning they have the option to screen multiple antibodies at lower cost, and then they have the option to leave reviews about the antibodies that they anonymously purchase, to help inform other researchers. Click here or visit http://oneworldlab.com/about-one-world-lab/news/2017/02/20/the-importance-of-sourcing-the-correct-antibodies-for-stem-cell-research/ to read the Q&A with Andrew Crain: Lab Manager in Snyder Lab at the Burnham Institute for Medical Research Stem cell research holds untold potential towards new cures and treatments for numerous diseases that have no remedies today. This future where once untreatable conditions that affected us are now finally curable requires an unwavering foundation in the fundamental understanding of how complex biological systems work. The only way this can occur in a reasonable timeframe is if the industry that supplies biomedical research tools and reagents, like antibodies, improves the way it operates. Without a systemic change, the biomedical research profession will continue to suffer from high levels of irreproducible science.


Kraushaar D.C.,University of Georgia | Yamaguchi Y.,Burnham Institute for Medical Research | Wang L.,University of Georgia
Journal of Biological Chemistry | Year: 2010

Pluripotent embryonic stem cells (ESCs) must select between alternative fates of self-renewal and lineage commitment at each division during continuous proliferation. Heparan sulfate (HS) is a highly sulfated polysaccharide and is present abundantly on the ESC surface. In this study, we investigated the role of HS in ESC self-renewal by examining Ext1-/- ESCs that are deficient in HS. We found that Ext1-/- ESCs retained their self-renewal potential but failed to transit from self-renewal to differentiation upon removal of leukemia inhibitory factor. Furthermore, we found that the aberrant cell fate commitment is caused by defects in fibroblast growth factor signaling, which directly retained high expression of the pluripotency gene Nanog in Ext1-/- ESCs. Therefore, our studies identified and defined HS as a novel factor that controls ESC fate commitment and also delineates that HS facilitates fibroblast growth factor signaling, which, in turn, inhibits Nanog expression and commits ESCs to lineage differentiation. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Hansen M.,Burnham Institute for Medical Research | Kennedy B.K.,Buck Institute for Research on Aging
Trends in Cell Biology | Year: 2016

Once thought to be impossible, it is now clear that changing the activity of several conserved genetic pathways can lead to lifespan extension in experimental organisms. In humans, however, the goal is to extend healthspan, the functional and disease-free period of life. Are the current pathways to lifespan extension also improving healthspan? © 2016.


Gonzalez R.,Scripps Research Institute | Lee J.W.,Scripps Research Institute | Snyder E.Y.,Burnham Institute for Medical Research | Schultz P.G.,Scripps Research Institute
Angewandte Chemie - International Edition | Year: 2011

Self-renewal promoter: Using a high-throughput screening assay, the small molecule dorsomorphin (see scheme) was identified as a positive regulator of human embryonic stem cell (hESC) self-renewal. It is shown that dorsomorphin promotes hESC self-renewal by antagonizing autocrine BMP signaling. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Chung T.D.Y.,Burnham Institute for Medical Research
Combinatorial Chemistry and High Throughput Screening | Year: 2014

There has been increased concern that the current "blockbuster" model of drug discovery and development practiced by "Big Pharma" are unsustainable in terms of cost (> 1 billion/approved drug) and time to market (10 - 15 years). The recent mergers and acquisitions (M&A), shuttering of internal research programs, closure of "redundant" sites of operations, senior management turnover and continued workforce reductions among the top 10 major pharmaceutical companies reflect draconian responses to reduce costs. However, the resultant exodus of intellectual capital, loss in motivation and momentum, and exit from early stage discovery programs by pharmaceutical companies has contributed to an "innovation deficit". Disease advocacy groups, investment communities and the government are calling for new innovative business models to address this deficit. In particular they are looking towards academia and clinical trials centers to catalyze new innovations in translational research. Indeed over the last decade many academic institutions have launched drug discovery centers largely comprising high-throughput screening (HTS) to accelerate "translational" research. A major impetus for this "open innovation" effort has been the National Institutes of Health (NIH) "Roadmap" and Molecular Libraries Initiative/Program (MLI/MLP), which is in its last year, and will be transitioned into the National Center for the Advancement of Translational Sciences (NCATS). With the end of Roadmap funding, general reduction in Federal government funding and its recent sequestration, academic drug discovery centers are being challenged to become selfsustaining, adding financial value, while remaining aligned with the missions of their respective academic non-profit institutions. We describe herein, a brief history of our bi-coastal Conrad Prebys Center for Chemical Genomics (Prebys Center) at the Sanford|Burnham Medical Research Institute (SBMRI), the key components of its infrastructure, core competencies of its fully integrated drug discovery expertise, best practices adopted in our day-to-day operations, and finally some of our current funding and collaboration and/or strategic alliance models for pre-competitive drug discovery with other academic/clinical partners, other governmental agencies, and with pharmaceutical and biotechnology companies. © 2014 Bentham Science Publishers.


Polewski M.D.,University of California at San Diego | Johnson K.A.,Genomics Institute of the Novartis Research Foundation | Foster M.,University of California at San Diego | Millan J.L.,Burnham Institute for Medical Research | Terkeltaub R.,University of California at San Diego
Bone | Year: 2010

Introduction: The physiologic selectivity of calcification in bone tissue reflects selective co-expression by osteoblasts of fibrillar collagen I and of tissue nonspecific alkaline phosphatase (TNAP), which hydrolyzes the calcification inhibitor pyrophosphate (PPi) and generates phosphate (Pi). Humans and mice deficient in the PPi-generating ecto-enzyme NPP1 demonstrate soft tissue calcification, occurring at sites of extracellular matrix expansion. Significantly, the function in osteoblasts of cytosolic inorganic pyrophosphatase (abbreviated iPPiase), which generates Pi via PPi hydrolysis with neutral pH optimum, remains unknown. We assessed iPPiase in Enpp1-/- and wild type (WT) mouse osteoblasts and we tested the hypothesis that iPPiase regulates collagen I expression. Methods: We treated mouse calvarial osteoblasts with ascorbate and β-glycerol phosphate to promote calcification, and we assessed cytosolic Pi and PPi levels, sodium-dependent Pi uptake, Pit-1 Pi co-transporter expression, and iPPiase and TNAP activity and expression. We also assessed the function of transfected Ppa1 in osteoblasts. Results: Inorganic pyrophosphatase but not TNAP was elevated in Enpp1-/- calvariae in situ. Cultured primary Enpp1-/- calvarial osteoblasts demonstrated increased calcification despite flat TNAP activity rather than physiologic TNAP up-regulation seen in WT osteoblasts. Despite decreased cytosolic PPi in early culture, Enpp1-/- osteoblasts maintained cytosolic Pi levels comparable to WT osteoblasts, in association with increased iPPiase, enhanced sodium-dependent Pi uptake and expression of Pit-1, and markedly increased collagen I synthesis. Suppression of collagen synthesis in Enpp1-/- osteoblasts using 3,4-dehydroproline markedly suppressed calcification. Last, transfection of Ppa1 in WT osteoblasts increased cytosolic Pi and decreased cytosolic but not extracellular PPi, and induced both collagen I synthesis and calcification. Conclusions: Increased iPPiase is associated with "Pi hunger" and increased calcification by NPP1-deficient osteoblasts. Furthermore, iPPiase induces collagen I at the levels of mRNA expression and synthesis and, unlike TNAP, stimulates calcification by osteoblasts without reducing the extracellular concentration of the hydroxyapatite crystal inhibitor PPi.


Roughley P.J.,McGill University | Lamplugh L.,McGill University | Lee E.R.,McGill University | Matsumoto K.,Burnham Institute for Medical Research | Yamaguchi Y.,Burnham Institute for Medical Research
Spine | Year: 2011

Study Design. Histologic analysis of spine development in cartilage-specific knockout mice. Objective. To evaluate the role hyaluronan produced by hyaluronan synthase-2 (Has2) in spine development. Summary of Background Data. The Has2 gene is responsible for most hyaluronan production throughout the body, including the skeleton. However, it is not possible to study the involvement of hyaluronan in skeletal development using constitutive Has2 knockout mice, as the embryonic mice die early before skeletal development has occurred. This problem can be overcome by the use of cartilage-specific knockout mice. Methods. Mice possessing fl oxed Has2 genes were crossed with mice expressing Cre recombinase under control of the type II collagen promoter to generate cartilage-specific Has2 knockout mice. Spine development was studied by histology. Results. Knockout mice died near birth and displayed severe abnormality in skeletal development. The spine showed defects in vertebral body size and the formation of the intervertebral discs. There was no evidence for the formation of an organized primary center of ossification within the vertebrae, and the appearance and organization of the hypertrophic chondrocytes was abnormal. Although no organized endochondral ossification appeared to be taking place, there was excessive bone formation at the center of the vertebrae. There was also a generalized increased cellularity of the vertebral cartilage and a corresponding decrease in the abundance of extracellular matrix. The nucleus pulposus of the intervertebral discs were less flattened than in the control mice and possessed an increased amount of large vacuolated cells. Remnants of the notochord could also be seen between adjacent discs. Conclusion. Hyaluronan production by Has2 is essential for normal vertebral and intervertebral disc development within the spine, and the absence of this synthase impairs the organization of both soft and hard tissue elements. Copyright © 2011 Lippincott Williams & Wilkins.

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