IMPACT OF AGING, ISCHEMIA AND CYTOKINES ON WOUND HEALING

描述(摘自申请者的摘要)：慢性无法愈合的伤口 这是老年人普遍存在的一个主要健康问题。局部组织 低氧，由糖尿病、静脉等潜在的健康问题引起 瘀血和外周血管疾病，是伴随所有 临床环境中的慢性创面类型。调查员的长期工作 目标是开发预防和治疗慢性伤口的方法 在了解老年心绞痛发病机制的基础上 慢性创面与生长因子在协调创面愈合中的作用 在慢性伤口微环境中。初步研究的重点是 建立缺氧组织环境的小鼠缺血模型 用于伤口愈合研究。使用这种模型和细胞培养，研究人员 以转化生长因子-β和基质金属蛋白酶的缺血调节为特征 在幼年动物和细胞中的表达。他们的总体假设是组织 缺氧对老化系统的伤口愈合产生负面影响，具有特异性 抑制生长因子转化生长因子-β1的促愈合作用。他们还进一步 假设这种损伤发生在转化生长因子-β1的表达和信号水平 部分地通过影响转化生长因子-β1的类型控制而限制愈合的转导 I型胶原表达和基质金属蛋白酶(MMPs)表达/活性。 控制I型胶原的表达和基质金属蛋白酶的活性是正常的 治愈的过程。这一假说将通过缺血皮瓣伤口进行检验。 在一个衰老的小鼠模型中。这项提案提出了旨在 阐明衰老系统中改变的细胞和分子机制 影响转化生长因子-β1在伤口愈合中的正常作用。他们的具体目标是 (1)研究缺血对老龄小鼠创面愈合的影响 并检测缺氧对转化生长因子-β亚型和转化生长因子-β的影响 伤口组织和液体中的受体；(2)检测下游基因的表达 转化生长因子-β1的效应基因，尤其是胶原和胶原降解基质 金属蛋白酶(MMPs)在老年小鼠缺血创面中的表达；(3)研究 低氧损伤老年小鼠创面愈合的分子细胞基础 老年小鼠皮肤原代培养的活体观察 成纤维细胞检测缺氧对早期转化生长因子-b信号转导的调节； (4)研究胶原和基质对缺氧的调节作用。 金属蛋白酶在衰老小鼠真皮成纤维细胞中的表达及意义 转化生长因子-β1在这些变化中的潜在作用。

DESCRIPTION (adapted from applicant's abstract): Chronic non-healing wounds are a major health problem commonly found in the elderly population. Local tissue hypoxia, resulting from underlying health problems such as diabetes, venous stasis and peripheral vascular disease, is a common feature accompanying all types of chronic wounds in the clinical setting. The investigator's long-term goal is to develop methods for the prevention and treatment of chronic wounds in the elderly based on an understanding of pathobiological mechanisms of chronic wounds and the function of growth factors in coordinating wound healing in the chronic wound microenvironment. Preliminary studies have focused on developing an ischemic murine model to generate a hypoxic tissue environment for wound healing studies. Using this model and cell culture, the investigators have characterized ischemic modulation of TGF-b and matrix metalloproteinase expression in young animals and cells. Their overall hypothesis is that tissue hypoxia negatively impacts wound healing in aged systems, with specific impairment of the pro-healing effects of the growth factor TGF-b1. They further hypothesize this impairment occurs at the level of TGF-b1 expression and signal transduction that, in part, limits healing by affecting TGF-b1 control of type I collagen expression and matrix metalloproteinase (MMP) expression/ activity. Control of type I collagen expression and MMP activity is required for a normal healing process. This hypothesis will be tested using the ischemic flap wound in an aged murine model. This proposal presents experiments designed to elucidate the cellular and molecular mechanisms altered in aged systems that affect the normal role of TGF-b1 in wound healing. Their specific aims are to (1) characterize the effect of ischemia on the wound healing of aged mouse wounds, and examine hypoxia-modulated alterations of TGF-b isoforms and TGF-b receptors in wound tissue and fluid; (2) examine expression of downstream effector genes of TGF-b1, specifically collagen and collagen-degrading matrix metalloproteinases (MMPs), in aged mouse ischemic wounds; (3) investigate the molecular and cellular basis for hypoxia-impaired wound healing in aged mice by extending in vivo observations to primary cultures of aged murine dermal fibroblasts to examine hypoxic modulation of early TGF-b signal transduction; (4) to investigate the hypoxia modulation of collagen and matrix metalloproteinase expression in aged murine dermal fibroblasts and the potential role of TGF-b1 in mediating these changes.