IMPACT OF AGING, ISCHEMIA AND CYTOKINES ON WOUND HEALING

衰老、缺血和细胞因子对伤口愈合的影响

• 批准号: 6417826
• 负责人: THOMAS Anthony MUSTOE
• 金额: $ 6.18万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6417826
• 关键词: aging; animal old age; biological signal transduction; chronic disease /disorder; collagen; collagenase; cytokine; disease /disorder model; fibroblast growth factor; fibroblasts; gel electrophoresis; gene expression; growth factor receptors; histology; hypoxia; ischemia; laboratory mouse; receptor expression; skin ulcer; tissue /cell culture; transforming growth factors; wound healing

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.

描述（改编自申请人摘要）：慢性不愈合伤口是 这是长者普遍面对的一个主要健康问题。局部组织 缺氧，由潜在的健康问题，如糖尿病，静脉 瘀血和外周血管病变，是伴随所有 临床环境中的慢性伤口类型。调查员的长期 目标是开发预防和治疗慢性伤口的方法 在老年人的基础上，了解病理生物学机制， 慢性创面与生长因子在创面愈合中的协调作用 在慢性伤口微环境中。初步研究集中在 开发缺血性鼠模型以产生缺氧组织环境 用于伤口愈合研究。使用这种模型和细胞培养，研究人员 已经表征了TGF-β和基质金属蛋白酶的缺血性调节 在年轻的动物和细胞中表达。他们的总体假设是 缺氧对老年系统的伤口愈合有负面影响， 生长因子TGF-β 1的促愈合作用的损害。他们进一步 假设这种损伤发生在TGF-β 1表达和信号水平， 在某种程度上，通过影响TGF-b1对 I胶原表达和基质金属蛋白酶（MMP）表达/活性。 控制I型胶原蛋白表达和MMP活性是正常的 愈合过程这一假设将使用缺血皮瓣伤口进行检验 在老年小鼠模型中。该提案提出的实验旨在 阐明在老化系统中改变的细胞和分子机制， 影响TGF-β 1在伤口愈合中的正常作用。其具体目标是 (1)缺血对老龄小鼠伤口愈合的影响 创伤，并检查TGF-β亚型和TGF-β受体的缺氧调节的改变。 受体在伤口组织和液体中的表达;（2）检查下游受体的表达。 TGF-β 1的效应基因，特别是胶原和胶原降解基质 金属蛋白酶（MMPs）在老年小鼠缺血性创面中的表达;（3）研究MMPs在老年小鼠缺血性创面中的表达。 缺氧损伤老年小鼠伤口愈合的分子和细胞基础 将体内观察扩展到老年鼠真皮的原代培养物 成纤维细胞检测早期TGF-β信号转导的低氧调节; (4)研究胶原和基质的缺氧调节作用 老年小鼠皮肤成纤维细胞金属蛋白酶的表达及意义 TGF-β 1在介导这些变化中的潜在作用。