Hypoxic Control of Collagen Biosynthesis

描述（由申请人提供）：本申请涉及广泛的挑战领域（09）健康差异和特定的挑战主题，09-AR-105：瘢痕疙瘩。瘢痕疙瘩是伤口愈合的病理形式，经常毁容，其中存在结缔组织（主要是胶原）的过度沉积。缺氧是瘢痕疙瘩的主要特征。因此，了解缺氧与胶原沉积之间的关系将为了解瘢痕疙瘩的发病机制和治疗提供依据。缺氧和胶原形成之间的一个公认的联系是通过缺氧刺激的转录因子缺氧诱导因子（HIF）的激活。HIF主要通过其亚基调节，在常氧条件下，其组成性脯氨酰羟基化，这是一种靶向HIF-降解的修饰。在缺氧条件下，这种固有的氧依赖性修饰被阻止，导致HIF-1 α的稳定。HIF-然后反式激活大量基因，包括那些编码胶原蛋白链以及胶原蛋白修饰酶的基因。使用脯氨酰羟化来调节缺氧诱导因子-引发了一个问题：它是否可能在缺氧反应中发挥额外的作用。在这个建议中，我们提供的证据表明，脯氨酰羟基化直接调节胶原蛋白修饰酶的活性。我们的具体目标是确定该酶中脯氨酰羟化的调节位点，鉴定修饰该酶的脯氨酰羟化酶，并检查其他胶原修饰酶是否受脯氨酰羟化的调节。我们预期这些研究将提高我们对瘢痕疙瘩发病机制、胶原代谢和氧稳态的认识。宾夕法尼亚大学医学院为当地经济做出了巨大贡献。2008年，医学院创造了37，000个就业机会和54亿美元的区域经济活动，该地区训练有素的劳动力为宾夕法尼亚大学840个开放的研究职位提供了24，600多份申请。目前的提案将创造两个就业岗位。这个项目旨在了解瘢痕疙瘩形成的基础，一种无序的伤口愈合形式。在瘢痕疙瘩中，低氧张力和胶原沉积都存在，我们将研究低氧张力如何通过改变胶原修饰酶的活性直接影响胶原的生物合成。这些研究将有助于我们理解瘢痕疙瘩，更一般地说，对低氧张力的反应。

DESCRIPTION (provided by applicant):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.