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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.

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.

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.

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.

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.

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