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老化的分子基础和功能影响。皮肤，像所有人类器官一样，随着时间的推移而发生有害的变化。皮肤的自然老化主要表现为变薄，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，并赋予结构，强度和弹性。胶原蛋白的依赖性损失导致脆性增加，从而使皮肤更容易擦伤并阻碍伤口愈合。美国人口老龄化使得脆弱皮肤的医疗护理成为日益增长的公共卫生问题。除了是人体最大的器官外，皮肤也很容易用于研究。皮肤的这些独特性质为研究人类衰老的分子机制提供了机会。衰老的自由基理论认为，自然衰老是由细胞损伤驱动的，细胞损伤是由有氧代谢产生的活性氧（ROS）氧化引起的。我们发现，活性氧水平升高，在体内老化的人皮肤成纤维细胞。成纤维细胞是产生I型胶原的主要细胞类型。此外，我们发现，TGF-2/SMAD/CTGF轴，这是驱动皮肤中I型胶原蛋白产生的主要调控网络，在老年人皮肤中受损。这种损伤是由SMAD 3（其是TGF-2作用的下游效应物）的表达降低和结缔组织生长因子（CTGF）（其是与TGF-2协同作用以调节I型胶原表达的多功能蛋白质）的表达降低引起的。此外，我们发现，原代培养的人真皮成纤维细胞的轻度、短期氧化暴露引起永久性细胞改变，其密切模拟在体内老化皮肤中的成纤维细胞中观察到的那些改变;即，增加的ROS、减少的SMAD 3、减少的CTGF和减少的I型胶原蛋白表达。基于这些观察结果，我们假设增加的ROS减少了SMAD 3和CTGF的表达，这导致老年人皮肤成纤维细胞中I型胶原蛋白产生的减少。我们提出了四个具体目标来检验这一假设：1）确定体内人皮肤成纤维细胞中ROS、SMAD 3、CTGF和I型胶原蛋白产生的年龄相关改变，2）确定体内老化人皮肤中局部抗氧化剂降低ROS水平、减轻TGF-2/SMAD/CTGF轴损伤和诱导I型胶原蛋白产生的能力，3）确定氧化暴露降低人滑雪成纤维细胞中SMAD 3、CTGF和I型胶原表达的分子机制，和4）确定CTGF调节I型胶原表达的分子机制。从拟议的研究结果将提供重要的见解1）人类皮肤老化的发病年龄，2）局部抗氧化剂的分子作用，3）氧化暴露调节TGF-2/SMAD/CTGF轴的机制，和4）CTGF与TGF-2合作调节I型胶原蛋白表达的分子基础。公共卫生相关性：拟议研究的长期、广泛目标是了解皮肤结缔组织老化的分子基础。皮肤胶原蛋白的皮肤依赖性损失导致皮肤脆性增加，从而使皮肤更容易擦伤并阻碍伤口愈合。美国人口的老龄化使得脆弱皮肤的医疗护理成为日益增长的公共卫生问题。