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)健康差距，以及具体的挑战主题，09-AR-105：瘢痕疙瘩。瘢痕疙瘩是伤口愈合的一种病理形式，通常是毁容的，其中有结缔组织过度沉积，主要是胶原。低氧是瘢痕疙瘩的主要特征。因此，了解低氧与胶原沉积的关系将为理解瘢痕疙瘩的发病机制和治疗提供基础。低氧和胶原形成之间的一个公认的联系是通过低氧刺激转录因子低氧诱导因子(HIF)的激活。HIF主要通过其亚单位调节，在常氧条件下，该亚单位被结构性地羟化，这是一种针对HIF的修饰，用于降解HIF。在低氧条件下，这种固有的氧依赖的修饰被阻止，导致HIF-的稳定。HIF-然后反式激活许多基因，包括那些编码胶原链和胶原修饰酶的基因。使用脯氨酸羟化来调节HIF-提出了一个问题，即它是否可能在缺氧反应中发挥额外的作用。在这项提案中，我们提供了脯氨酸羟化直接调节胶原修饰酶活性的证据。我们的具体目标是确定该酶中Pro羟化的调节位点，鉴定修饰该酶的Pro羟基酶，并检查其他胶原修饰酶是否受Pro羟化调控。我们预计，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了解。宾夕法尼亚大学医学院为当地经济做出了巨大贡献。2008年，该医学院创造了3.7万个就业机会和54亿美元的区域经济活动，该地区训练有素的劳动力仅为840个空缺的宾夕法尼亚大学员工研究职位就产生了超过24600份申请。目前的提案将创造两个就业机会。这个项目试图了解瘢痕疙瘩形成的基础，瘢痕疙瘩是一种混乱的伤口愈合形式。在瘢痕疙瘩中，低氧压和胶原沉积都存在，我们将研究低氧压是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的。这些研究将有助于我们对瘢痕疙瘩的了解，更广泛地说，有助于了解对低氧分压的反应。

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.