2009 Marta Marx Eradication of Scleroderma Award Recipient

Frank Lee, M.D.
University of Pittsburgh, Pittsburgh, Pa.

"Hypoxic Control of the Extracellular Matrix"

Scleroderma is characterized by excessive fibrosis in multiple tissues, which gives rise to the stiffness and thickening, leading to the devastating consequences of this disease.  Understanding of how this fibrosis occurs will lead to a greater understanding of how this disease develops and provide a foundation for possible therapies.  It is known that in affected tissues in scleroderma, there are areas that lack oxygen, which in turn are thought to promote fibrosis by increasing the molecules that are present in fibrosed tissues.  One such molecule is collagen, one of the most abundant in these areas.  Collagen itself is modified by other proteins, and these modifications are essential for collagen stability.  We speculate in the present application that a collagen-modifying protein itself is directly activated by hypoxia.  We propose to perform experiments that will determine the exact molecular nature by which this protein is activated and the protein that activates it.  We also propose to examine other collagen-modifying enzymes in a similar manner.  We anticipate that these studies will define a new pathway by which low oxygen leads to increased collagen deposition, and hence fibrosis.  These findings will have implications for understanding fibrosis, a signature event of scleroderma.