Regulation of Extracellular Matrix Homeostatsis in Skin Aging

皮肤衰老过程中细胞外基质稳态的调节

• 批准号: 7907781
• 负责人: GARY J FISHER
• 金额: $ 31.36万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907781
• 关键词: Age; Age of Onset; Aging; Antioxidants; Behavior Control; Biochemical; Blood Vessels; Caring; Cell Culture Techniques; Cell Respiration; Cells; Collagen; Collagen Type I; Connective Tissue; Controlled Environment; Contusions; Data; Dermal; Dermis; Elderly; Epidermis; Epithelium; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Free Radicals; Goals; Hair follicle structure; Human; Immune; Impairment; MADH3 gene; Mechanics; Mediating; Medical; Molecular; Nerve; Neurons; Organ; Pathway interactions; Population; Production; Property; Proteins; Public Health; Reactive Oxygen Species; Regulation; Research; Sebaceous Glands; Signal Pathway; Signal Transduction; Skiing; Skin; Skin Aging; Smooth Muscle Myocytes; Structural Protein; Structure; Study models; Sweat Glands; Testing; Time; Type I Procollagen; Wound Healing; age related; aged; appendage; base; cell behavior; cell type; connective tissue growth factor; in vivo; insight; oxidation; public health relevance; theories

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to understand molecular basis and functional impact of skin connective tissue aging. Skin, like all human organs, undergoes deleterious alterations as a consequence of the passage of time. Natural aging of skin is manifested primarily by thinning, largely due to loss of type I collagen in the dermis. Type I collagen is the most abundant protein in skin and confers structure, strength and resiliency. Age-dependent loss of collagen causes increased fragility and thereby makes skin more susceptible to bruising and impedes wound healing. Aging of the US population makes medical care of fragile skin a growing public health concern. In addition to being the largest human organ, skin is readily accessible for study. These unique properties of skin provide the opportunity study molecular mechanisms of aging in humans. The free radical theory of aging posits that natural aging is driven by cellular damage that results from oxidation by reactive oxygen species (ROS) that are generated as a consequence of aerobic metabolism. We find that ROS levels are elevated in aged human skin fibroblasts in vivo. Fibroblasts are the major cell type that produces type I collagen. In addition, we find that the TGF-2/SMAD/CTGF axis, which is the major regulatory network that drives type I collagen production in skin, is impaired in aged human skin. This impairment results from decreased expression of SMAD3, which is a downstream effector of TGF-2 actions, and reduced expression of connective tissue growth factor (CTGF), which is a multi-functional protein that acts in concert with TGF-2 to regulate type I collagen expression. Furthermore, we find that mild, short-term oxidative exposure of primary cultured human dermal fibroblasts causes permanent cellular alterations that closely mimic those observed in fibroblasts in aged skin in vivo; namely, increased ROS, reduced SMAD3, reduced CTGF, and reduced type I collagen expression. Based on these observations, we hypothesize that increased ROS, reduces expression of SMAD3 and CTGF, which results in reduction of type I collagen production, in fibroblasts in aged human skin. We propose four Specific Aims to test this hypothesis: 1) determine age-related alterations of ROS, SMAD3, CTGF, and type I collagen production, in human skin fibroblasts in vivo, 2) determine the ability of topical anti-oxidant to reduce ROS levels, mitigate impairment of the TGF-2/SMAD/CTGF axis, and induce type I collagen production, in aged human skin in vivo, 3) determine molecular mechanisms by which oxidative exposure reduces SMAD3, CTGF and type I collagen expression in human ski fibroblasts, and 4) determine molecular mechanisms by which CTGF regulates type I collagen expression. The results from the proposed studies will provide important insights regarding 1) the age of onset of human skin aging, 2) molecular actions of topical antioxidant, 3) mechanisms by which oxidative exposure regulates the TGF-2/SMAD/CTGF axis, and 4) molecular basis by which CTGF cooperates with TGF-2 in the regulation of type I collagen expression. PUBLIC HEALTH RELEVANCE: The long-term, broad goal of the proposed research is to understand the molecular basis of skin connective tissue aging. Age-dependent loss of skin collagen causes increased skin fragility and thereby makes skin more susceptible to bruising and impedes wound healing. The aging of the US population makes medical care of fragile skin a growing public health concern.

描述（由申请人提供）：拟议研究的长期目标是了解皮肤结缔组织衰老的分子基础和功能影响。像所有人类器官一样，皮肤会由于时间的流逝而经历有害的改变。皮肤的自然衰老主要通过变薄表现出来，这主要是由于真皮中I型胶原蛋白的损失。 I型胶原蛋白是皮肤中最丰富的蛋白质，并具有结构，强度和弹性。胶原蛋白的年龄依赖性损失会增加脆弱性，从而使皮肤更容易受到瘀伤的影响，并阻碍伤口愈合。美国人口的老龄化使对脆弱皮肤的医疗护理成为日益增长的公共健康问题。除了成为最大的人体器官外，皮肤还可以轻松进行研究。皮肤的这些独特特性提供了人类衰老的机会研究分子机制。衰老的自由基理论表明，自然衰老是由细胞损伤驱动的，细胞损伤是由活性氧（ROS）氧化引起的，这些氧气是有氧代谢而产生的。我们发现，体内人类皮肤成纤维细胞的老年皮肤成纤维细胞升高。成纤维细胞是产生I型胶原蛋白的主要细胞类型。此外，我们发现TGF-2/SMAD/CTGF轴是驱动皮肤中I型胶原蛋白产生的主要调节网络，在老年人皮肤中受损。这种障碍是由SMAD3表达降低引起的，SMAD3是TGF-2作用的下游效应子，以及结缔组织生长因子（CTGF）的表达降低，这是一种多功能蛋白，与TGF-2一起起作用以调节I型胶原蛋白表达。此外，我们发现原发性培养的人真皮成纤维细胞的轻度，短期氧化暴露会导致永久性细胞改变，这些细胞改变与体内老化皮肤的成纤维细胞中观察到的那些相关。也就是说，ROS增加，SMAD3减少，CTGF降低和I型胶原蛋白表达降低。基于这些观察结果，我们假设增加了ROS，降低了SMAD3和CTGF的表达，从而导致I型胶原蛋白产生的成纤维细胞减少人类皮肤的成纤维细胞。 We propose four Specific Aims to test this hypothesis: 1) determine age-related alterations of ROS, SMAD3, CTGF, and type I collagen production, in human skin fibroblasts in vivo, 2) determine the ability of topical anti-oxidant to reduce ROS levels, mitigate impairment of the TGF-2/SMAD/CTGF axis, and induce type I collagen production, in aged human skin in vivo, 3）确定氧化暴露减少人类滑雪成纤维细胞中SMAD3，CTGF和I型胶原蛋白表达的分子机制，以及4）确定CTGF调节I型胶原蛋白表达的分子机制。 The results from the proposed studies will provide important insights regarding 1) the age of onset of human skin aging, 2) molecular actions of topical antioxidant, 3) mechanisms by which oxidative exposure regulates the TGF-2/SMAD/CTGF axis, and 4) molecular basis by which CTGF cooperates with TGF-2 in the regulation of type I collagen expression.公共卫生相关性：拟议研究的长期，广泛的目标是了解皮肤结缔组织衰老的分子基础。依赖年龄的皮肤胶原蛋白会导致皮肤脆弱性增加，从而使皮肤更容易受伤并阻碍伤口愈合。美国人口的衰老使对皮肤脆弱的皮肤的护理成为日益增长的公共健康问题。