Role of O2 in PDGFRb expression and function in aging.

描述(由申请者提供)：我们的长期目标是确定衰老过程中伤口延迟愈合的机制，希望开发新的治疗方法。高压氧长期以来一直被用于治疗难以愈合的伤口，并在治愈老年患者的伤口方面显示出良好的效果。然而，人们对其中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高压氧提高伤口愈合率的机制。我们的实验室已经证明，PDGFRb在来自老年捐赠者的成纤维细胞中的表达减少。增殖减少与功能性PDGFRb表达减少相关。高压氧治疗通过增加PDGFRb的数量和成纤维细胞的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)依赖的机制上调PDGFRb的表达。在动物和人体研究中，伤口愈合不需要任何产物，而且没有足够的产物与伤口愈合延迟有关。我们的假设是，年龄相关的PDGFRb表达和功能障碍可能会被HBO以一种非依赖的方式纠正。我们计划定义PDGFRb启动子中的氧反应元件(S)(ORE)，并确定这些元件在来自老年人、年轻人和新生儿捐赠者的人成纤维细胞中是否具有不同的功能。我们将重点介绍我们的体外模型系统，并具体描述成纤维细胞的作用。这些研究的发现将对衰老的新治疗方法具有重要意义。

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.