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，以及具体的挑战主题，09- ar -105：瘢痕疙瘩。瘢痕疙瘩是一种伤口愈合的病理形式，通常毁容，其中有过多的结缔组织沉积，主要是胶原蛋白。缺氧是瘢痕疙瘩的主要特征。因此，了解缺氧与胶原沉积的关系将为了解瘢痕疙瘩的发病机制和治疗提供基础。缺氧与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主要通过其亚基进行调节，在常压条件下，亚基是聚丙基羟基化的，这是一种针对HIF-进行降解的修饰。在缺氧条件下，这种固有的氧依赖性的修饰被阻止，导致HIF-稳定。HIF-随后会激活大量基因，包括编码胶原蛋白链和胶原蛋白修饰酶的基因。丙基羟基化对HIF-的调节提出了一个问题，即它是否在缺氧反应中发挥了额外的作用。在这个提议中，我们提供证据表明脯氨酰羟基化直接调节胶原修饰酶的活性。我们的具体目的是确定该酶中脯氨酸羟化的调节位点，确定修饰该酶的脯氨酸羟化酶，并检查其他胶原修饰酶是否受脯氨酸羟化的调节。我们期望这些研究将增强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，医学院为该地区创造了37,000个工作岗位和54亿美元的经济活动，该地区训练有素的劳动力为840个宾夕法尼亚大学的研究职位提供了超过24,600份申请。目前的提案将创造两个工作岗位。该项目旨在了解瘢痕疙瘩形成的基础，这是一种无序伤口愈合的形式。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对瘢痕疙瘩的理解，以及对低氧张力的反应。

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.