This application addresses broad Challenge Area (09) Health Disparities, and specific Challenge Topic, 09-AR-105: Keloids. Keloids are a pathologic form of wound healing, often disfiguring, in which there is excessive deposition of connective tissue, principally collagen. Hypoxia is a central feature of keloids. Hence, understanding the relationship between hypoxia and collagen deposition will provide the basis for understanding the pathogenesis of keloids and treating this disease. One well recognized link between hypoxia and collagen formation is through the hypoxia-stimulated activation of the transcription factor, Hypoxia Inducible Factor (HIF). HIF is regulated primarily through its subunit, which under normoxic conditions is constitutively prolyl hydroxylated, a modification which targets HIF- for degradation. Under hypoxic conditions, this modification, which is inherently oxygen dependent, is arrested, leading to stabilization of HIF-. HIF- then transactivates a multitude of genes, including those encoding for collagen chains as well as collagen-modifying enzymes. The use of prolyl hydroxylation to regulate HIF- raises the question of whether it may play additional roles in the hypoxic response. In this proposal, we provide evidence that prolyl hydroxylation directly regulates the activity of a collagen modifying enzyme.
Our Specific Aims are to determine the regulatory sites of prolyl hydroxylation in this enzyme, identify the prolyl hydroxylase that modifies the enzyme, and examine whether other collagen modifying enzymes are regulated by prolyl hydroxylation. We anticipate that these studies will enhance our knowledge of keloid pathogenesis, collagen metabolism, and oxygen homeostasis. The University of Pennsylvania School of Medicine contributes substantially to the local economy. In 2008, the School of Medicine created 37,000 jobs and $5.4 billion in regional economic activity, with the area's highly trained workforce producing more than 24,600 applications for just 840 open Penn staff research positions. The current proposal will create two jobs. This project seeks to understand the basis of keloid formation, a form of disordered wound healing. In keloids, low oxygen tension and collagen deposition are both present, and we will investigate how low oxygen tension directly influences the biosynthesis of collagen by changing the activity of a collagen modifying enzyme. These studies will contribute to our understanding of keloids and more, generally, the responses to low oxygen tension.
This project seeks to understand the basis of keloid formation, a form of disordered wound healing. In keloids, low oxygen tension and collagen deposition are both present, and we will investigate how low oxygen tension directly influences the biosynthesis of collagen by changing the activity of a collagen modifying enzyme. These studies will contribute to our understanding of keloids and more, generally, the responses to low oxygen tension.
