My research program focuses on the structure and function of type IV collagen, the major constitutent of basement membranes (BMs). BMs are a specialized form of extracellular matrix that compartmentalizes tissues and play an important role in tissue remodeling and morphogenesis. BM function is impaired in both hereditary and acquired diseases that affect type IV collagen. In Alport syndrome, a hereditary renal disease, the collagen genes are mutated. In Goodpasture syndrome, a rapidly progressive renal disease with lung hemorrhage, the collagen is the target for autoantibodies. In diabetes, the vascular complications of nephropathy and retinopathy also appear to involve this collagen.
Type IV collagen has recently emerged as a family of six homologous alpha-chains, designated alpha1 to alpha6. My research group discovered the alpha3 and alpha4 chains. The alpha3 chain is the target for autoantibodies in Goodpasture syndrome and the alpha5 chain is the target for autoantibodies in a novel autoimmune disease that causes renal disease and skin blistering. The alpha3, alpha4, and alpha5 chains are mutated in Alport syndrome causing defective assembly of a supramolecular network which leads to progressive renal failure. Recently we have shown that the code for the assembly of chain-specific networks resides within the noncollagenous (NC1) domain of the collagen chains. The three-dimensional structure of this domain was recently determined by x-ray crystallography, revealing novel information about structure and function. Most recently, we discovered that type IV collagen may represent an important new class of anti-angiogenic molecules for the treatment of neovascular diseases, such as tumor growth and metastasis. Our findings have led to the development of two drugs: Pyridorin, a molecule inhibitor for the treatment of diabetic renal disease now in phase II trials, and Angiocol an anti-angiogenesis agent that targets basal lamina, slated for a phase I trial next year. |