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|Daniel S. Greenspan, PhD|
Research SummaryExtracellular modulators of cellular behaviors in development, homeostasis, and disease
Our focus has been on genes and gene products important to vertebrate development and human disease. We have previously discovered a number of developmentally important genes, and determined their involvement in normal morphogenesis and in genetic abnormalities. For, example, we were involved in isolating and characterizing the locus for the disfiguring and ultimately fatal heritable skin disorder dystrophic epidermolysis bullosa. We've also found and helped characterize the locus for classic Ehlers-Danlos syndrome, which occurs in about 1 in 20,000 births and produces individuals with fragile connective tissues.
Much work in the lab currently focuses on extracellular regulatory proteins that control and orchestrate events as diverse as growth factor signaling and formation of the extracellular matrix (ECM). Such events are critical in adult vertebrates (e.g. for maintenance of the cardiovascular system, wound healing, turnover of the skeleton and synaptic plasticity) and are even more dynamic during development. One class of the regulatory molecules that we study comprises small families of proteases that activate and inactivate various growth factors, enzymes and extracellular structural macromolecules. An example is the BMP1/Tolloid-like family of proteinases (see the Figure, below). Another class comprises antagonists of signaling by members of the TGFb superfamily of growth factors. Three additional classes of regulatory molecules under study modify actions of the first two by as yet unclear mechanisms. Molecules we study play central roles in morphogenetic processes and defects in these proteins may underlie human disease. Our studies employ biochemical, genetic and developmental analyses, including characterizing standard and conditional "knockout" mice, and zebrafish and examining possible links between defects in genes of interest and human development and disease.
Current studies in the lab also include roles of extracellular proteins in adipocyte biology, diabetic symptoms, atherosclerosis, and organ transplant rejection. The latter two studies include translational studies of human patients. roteins for in vitro and cell culture assays of protein function; high throughput screens for protein:protein interactions; the production and characterization of standard and conditional "knockout" mice that have altered alleles for the genes of interest, and examination of possible links between defects in the genes we study and human developmental abnormalities.
Huang G, Greenspan DS. Roles of ECM in the function of metabolic tissues. Trends Endocrinol. Metab 23, 16-22 (2012).
Asharani PV, Keupp K, Semler O, Wang W, Li Y, Thiele H, Yigit G, Pohl E, Becker J, Frommolt P, Sonntag C, Altmüller J, Zimmermann K Greenspan DS, Akarsu NA, Netzer C, Schönau E, Wirth R, Hammerschmidt M, Nürnberg P, Wollnik B, Carney TJ. Attenuated BMP1 function compromises Osteogenesis, leading to bone fragility in humans and zebrafish. Am J Hum Genet 90, 661-674 (2012).
Kim B, Huang G., Ho W-B, Greenspan DS. Bone morphogenetic protein-1 processes insulin-like growth factor-binding protein 3. J. Biol. Chem. 286, 29014-29025 (2011).
Muir A, Greenspan, DS. Metalloproteinases in Drosophila to humans that are central players in developmental processes. J. Biol. Chem. 286, 41905-41911 (2011).
Huang G, Ge G, Wang D, Gopalakrishnan B, Butz DH, Colman RJ, Nagy A, Greenspan DS. α3(V) collagen is critical for glucose homeostasis due to effects in islets and peripheral tissues in mice. J. Clin. Invest. 121, 769-783 (2011).
Dart ML, Jankowska-Gan E, Huang G, Roenneburg DA, Keller M R, Torrealba JR, Rhoads A, Marshall¬, Case S, Kim B, Bobadilla JL, Haynes LD, Wilkes DS, Burlingham WJ, and Greenspan DS. IL-17-dependent Autoimmunity to collagen type V in atherosclerosis. Circ. Res. 107, 1106-1116 (2010).
Branam AM, Hoffman GG, Pelegri F, Greenspan DS. Zebrafish chordin-like and chordin are functionally redundant in regulating patterning of the dorsoventral axis. Dev. Biol. 341, 444-458 (2010).
Huang G, Zhang Y, Kim B, Ge G, Annis DS, Mosher DF, and Greenspan DS. Fibronectin binds and enhances the activity of bone morphogenetic protein 1. J. Biol. Chem. 284, 25879-25888 (2009).
Kobayashi K, Luo M, Zhang Y, Wilkes DC, Ge G, Grieskamp T, Yamada C, Liu T-C, Huang G, Basson CT, Kispert A, Greenspan DS, Sato TN. Secreted Frizzled Related Protein 2 is a procollagen C-proteinase enhancer with a role in fibrosis associated with myocardial infarction. Nature Cell Biol. 11, 46-55, 2009
Kobayashi, K, Luo M, Zhang Y, Wilkes DC, Gao G, Grieskamp T, Yamada C, Liu T-C, Huang G, Basson CT, Kispert A, Greenspan DS*, Sato, TN*. Secreted Frizzled Related Protein 2 is a procollagen C-proteinase enhancer with a role in fibrosis associated with myocardial infarction. Nature Cell Biol. 11, 46-55 (2009) (*Co-contributing authors).
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File last updated: August 2, 2012