Role of O2 in PDGFRb expression and function in aging.

O2 在 PDGFRb 表达和衰老功能中的作用。

• 批准号: 7076042
• 负责人: WENDE R REENSTRA
• 金额: $ 16.09万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076042
• 关键词: age difference; aging; biological signal transduction; cell proliferation; fibroblasts; genetic promoter element; genetic regulatory element; growth factor receptors; hyperbaric oxygen therapy; nitric oxide; oxygen; platelet derived growth factor; protein structure function; receptor expression; tissue /cell culture; tissue donors; wound healing

DESCRIPTION (provided by applicant): Our long-term goal is to define the mechanisms responsible for delayed wound healing in aging in hopes of developing novel therapies. Hyperbaric oxygen has long been utilized in treating the difficult to heal wounds and has shown promising results on healing wounds from aging individuals. However, very little is understood about the molecular mechanisms involved. We plan to study the mechanisms involved in HBO's increase in wound healing rates by focusing specifically on the expression and function of the platelet derived growth factor receptor-beta (PDGRB) in fibroblasts. Our laboratory has shown that PDGFRB expression is reduced in fibroblasts derived from older donors. Reduced proliferation correlates to a reduction in functional PDGFRB expressed. Hyperbaric oxygen treatment corrects the age associated defect by increasing both PDGFRB number and proliferation of fibroblasts. Our preliminary studies suggest that HBO upregulates PDGFRB expression through a nitric oxide (NO)-dependent mechanism. NO production is required for proper wound healing and insufficient NO production has been linked to delayed wound healing in both animal and human studies. Our hypothesis is that the age associated dysfunction in PDGFRB expression and function may be corrected by HBO in an NO-dependent manner. We plan to define the oxygen-responsive element(s) (ORE) within the PDGFRB promoter and determine whether these elements function differently in human fibroblasts derived from old, young, and newborn donors. We will focus on our in vitro model system and delineate the role of the fibroblast specifically. Findings from these studies will have important implications for novel therapeutic approaches in aging.

描述（由申请人提供）：我们的长期目标是确定衰老过程中伤口愈合延迟的机制，以期开发新的疗法。高压氧长期以来一直被用来治疗难以愈合的伤口，并且在治愈老年人的伤口方面显示出有希望的结果。然而，人们对所涉及的分子机制知之甚少。我们计划通过特别关注成纤维细胞中血小板衍生生长因子受体-β (PDGRB) 的表达和功能来研究 HBO 提高伤口愈合率的机制。我们的实验室表明，来自老年供体的成纤维细胞中的 PDGFRB 表达降低。增殖减少与功能性 PDGFRB 表达的减少相关。高压氧治疗通过增加 PDGFRB 数量和成纤维细胞增殖来纠正与年龄相关的缺陷。我们的初步研究表明 HBO 通过一氧化氮 (NO) 依赖性机制上调 PDGFRB 表达。一氧化氮的产生是伤口正常愈合所必需的，在动物和人类研究中，一氧化氮的产生不足与伤口愈合延迟有关。我们的假设是，与年龄相关的 PDGFRB 表达和功能障碍可以通过 HBO 以 NO 依赖性方式纠正。我们计划定义 PDGFRB 启动子内的氧响应元件 (ORE)，并确定这些元件在来自老年、年轻和新生儿供体的人类成纤维细胞中是否有不同的功能。我们将重点关注我们的体外模型系统，并具体描述成纤维细胞的作用。这些研究的结果将对衰老的新治疗方法产生重要影响。