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: 8512628
• 负责人: GARY J FISHER
• 金额: $ 28.48万
• 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/8512628
• 关键词: 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; theories

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-¿/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-¿ actions, and reduced expression of connective tissue growth factor (CTGF), which is a multi-functional protein that acts in concert with TGF-¿ 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-¿/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-¿/SMAD/CTGF axis, and 4) molecular basis by which CTGF cooperates with TGF-¿ in the regulation of type I collagen expression.

支撑研究的长期目标是了解皮肤的分子基础和功能影响 结缔组织老化，像所有人类器官一样，经历了有害的改变 时间的通过。 真皮中的胶原蛋白胶原蛋白是皮肤中最丰富的蛋白 和韧性。 容易受到瘀伤和阻碍伤口愈合的人。 皮肤越来越多，除了最大的人体器官之外，皮肤还可以使用 为了留下来。 人类。 来自有氧代谢而产生的活性氧（ROS）的氧化。 我们发现，体内人体皮肤纤维纤维的老化人物纤维中的ROS水平升高。 产生I型胶原蛋白的类型。 /SMAD/CTGF轴，这是主要的 驱动皮肤I型胶原蛋白产生的调节网络在老年人皮肤中受损。 损伤是由于SMAD3的表达降低而导致的，这是TGF- - 的下游行动， 连接连接的表达降低，这是一种可起作用的多功能蛋白 与TGF-¿对于常规的I胶原蛋白表达。 原发性培养的人真皮成纤维细胞的氧化暴露会导致细胞侵袭 密切模仿体内老化皮肤的纤维杂交中观察到的那些； 基于观察结果减少了CTGF和I型胶原蛋白的表达。 ROS增加，降低SMAD3和CTGF的表达，从而减少I型胶原蛋白 生产，在老年人皮肤中的成纤维细胞中。 确定ROS，SMAD3，CTGF和I型胶原蛋白产生的与年龄相关的变化，在人类皮肤中 体内纤维细胞，2）确定局部抗氧化剂降低ROS水平的能力，减轻损害 TGF- /smad/ctgf轴，并诱导I型胶原蛋白产生，体内老年人皮肤，3）确定 氧化暴露会降低SMAD3，CTGF和I型胶原蛋白表达的分子机制 人类滑雪纤维细胞和4）确定CTGF常规I型胶原蛋白的分子机制 表达。 人类皮肤老化，2）局部抗氧化剂的分子作用，3）氧化暴露的机制 调节TGF-¿ /smad/ctgf轴和4）CTGF与TGF-€合作的分子基础在 I型胶原蛋白表达的调节。