Elastin and Collagen in the Aging Process

衰老过程中的弹性蛋白和胶原蛋白

• 批准号: 6612782
• 负责人: Jeffrey M. Davidson
• 金额: $ 26.45万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-02-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6612782
• 关键词: Adenoviridae; aging; angiogenesis; bioluminescence; bone marrow transplantation; collagen; collagenase; crosslink; disease /disorder model; elastin; follistatin; gene expression; gene therapy; genetically modified animals; glycation; growth factor; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rabbit; laboratory rat; polymerase chain reaction; reporter genes; skin; transfection /expression vector; wound healing

DESCRIPTION (provided by applicant): Wound healing is delayed and impaired during aging, and multiple mechanisms converge to alter repair. Previous and continuing work has shown that growth factors and their genes can be used to accelerate the repair process. To improve the capacity to screen for vulnerary agents, we add a novel model, the bioluminescent mouse, in which luciferase reporter genes, driven by specific murine promoters such as collagen (COL1A2) and collagenase (MMP-13), emit photons from the site of repair that localize and quantify gene expression. The MMP-13 model will be further refined by defining upstream regulatory elements. New transgenic strains to identify a marker of aging skin and wounds, MMP-2, will be developed. Together with conventional wound healing models, these transgenic systems will allow kinetic, real-time analysis of the mechanism of activity of therapeutic genes in a noninvasive mode. Fibroblast growth factor delivered by gene gun and adenoviral vectors, will be used to observe the effects of a growth factor on specific matrix genes. Since the lag in wound healing can be primed by re-excision, we hypothesize that the age-related delay in repair is due to depletion of stem cells that may be derived from local or circulating sources. Fibroblast and angiogenic precursor cells will be traced in adoptive bone marrow transfer expenments using selective, bioluminescent or biochemical, transgenic markers of each lineage (collagen l/MMP-13; flk-1). Gene therapy is a promising strategy for treating problem wounds, and it is a powerful method for discovering molecules active in the process. Activin cDNA shows vulnerary activity. Genes for activin and its antagonist, follistatin, will be validated in conventional and transgenic models of wound repair using biolistic and adenoviral delivery systems. This pair of genes will act as a prototype for the application of gene therapy and transgenic, reporter animals to functional genomics. The extracellular matrix is altered in aging, including the accumulation of crosslinks due to nonenzymatic glycation. A novel breaker of advanced glycation endproduct crosslinking, will be tested for its ability to alter the biomechanical properties of skin and the rate of wound repair in an established rat model.

描述（由申请人提供）：伤口愈合被延迟和受损 在老化期间，多种机制会融合改变修复。以前和 继续工作表明，增长因素及其基因可用于 加速维修过程。提高筛选漏洞的能力 代理，我们添加了一种新型模型，即生物发光小鼠，其中荧光素酶 记者基因，由特定的鼠启动子（例如胶原蛋白（COL1A2））驱动 和胶原酶（MMP-13），从维修部位发射光子 并量化基因表达。 MMP-13模型将进一步完善 定义上游监管元素。新的转基因菌株以识别 将开发衰老的皮肤和伤口标记MMP-2。一起 常规伤口愈合模型，这些转基因系统将允许动力学， 实时分析A中治疗基因活性的机理 无创模式。基因枪和腺病毒传递的成纤维细胞生长因子 向量将用于观察生长因子对特定的影响 基质基因。由于可以通过重新拆卸伤口愈合中的滞后疗法，我们 假设与年龄相关的修复延迟是由于茎的耗尽 可能来自局部或循环源的细胞。成纤维细胞和 血管生成前体细胞将在收养的骨髓转移中追踪 使用选择性，生物发光或生化，转基因标记的支出 每个谱系（胶原蛋白L/MMP-13; FLK-1）。基因疗法是一种有前途的 治疗问题伤口的策略，这是一种强大的方法 在此过程中发现活跃的分子。激活素cDNA显示脆弱性 活动。激活素及其拮抗剂Follistatin的基因将得到验证 在常规和转基因模型中，使用生物学和 腺病毒输送系统。这对基因将充当 将基因疗法和转基因，记者动物应用于功能 基因组学。细胞外基质在衰老中发生了改变，包括 由于非酶糖基化而导致的交联的积累。一个新颖的破坏者 先进的糖基化末期交联，将测试其能力 改变皮肤的生物力学特性和伤口修复率 建立的大鼠模型。