Extracellular Matrix Remodeling During Aging

衰老过程中的细胞外基质重塑

• 批准号: 7846791
• 负责人: JANE M SOTTILE
• 金额: $ 18.83万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846791
• 关键词: Age; Aging; Area; Arthritis; Atherosclerosis; Biological; Biomechanics; Brain; Caveolae; Cell Proliferation; Cells; Chemotaxis; Chronic; Clathrin; Collagen; Cytoskeleton; Data; Degenerative polyarthritis; Dementia; Deposition; Development; Differentiation and Growth; Disease; Down-Regulation; Endocytosis; Endothelial Cells; Equilibrium; Extracellular Matrix; Extracellular Matrix Degradation; Extracellular Matrix Proteins; Fibrillar Collagen; Fibronectins; Generations; Heart; Heart failure; Heparan Sulfate Proteoglycan; Homeostasis; Hypertension; Inflammation; Integrins; Kidney; Lead; Liver; Maintenance; Malignant Neoplasms; Mechanics; Mediating; Metabolism; Normal tissue morphology; Organ; Osteoporosis; Physiological; Play; Process; Production; Property; Proteins; Proteoglycan; Public Health; Pulmonary Emphysema; Risk Factors; Role; Signal Transduction; Skin; Stroke; Structure; Tenascin; Testing; Tissues; Wound Healing; age related; angiogenesis; caveolin 1; cell behavior; cell growth; cell motility; extracellular; fibulin; functional decline; heparin proteoglycan; human morbidity; in vivo; insight; interest; migration; mortality; novel; polymerization; prevent; public health relevance; receptor mediated endocytosis; scaffold; tissue/cell culture; tumor growth

DESCRIPTION (provided by applicant): During aging there is a progressive decline in the function of most organs and tissues. Aging is also associated with a number of diseases including arthritis, dementia, heart failure, hypertension, and atherosclerosis. Age-related changes in the synthesis, deposition, turnover, and biomechanical properties of the extracellular matrix (ECM) are well documented. The ECM controls many aspects of cell behavior including cell migration, proliferation, differentiation and survival, and plays a critical role in the maintenance of normal tissue function and tissue repair. As such, age-related changes in ECM and ECM remodeling are likely to be major contributors to the age-related decline in angiogenesis and tissue repair. Our data show that the ECM protein, fibronectin (FN), regulates the deposition and turnover of other ECM molecules including collagen I, collagen III, thrombospondin, and heparin sulfate proteoglycans. Further, factors that regulate the polymerization of FN into the ECM regulate the stability and turnover of FN and collagen I matrix fibrils. There is an age-related increase in the synthesis and deposition of FN. Because FN is a key regulator of cell migration, cell proliferation, tissue mechanical properties, and ECM composition and stability, age-related alterations in FN metabolism are likely to be a major contributor to age-related changes in cell and tissue function. Our data show that FN matrix turnover occurs through endocytosis and intracellular degradation, and is regulated by both caveolin-1 and 21 integrins. Age-related decreases in caveolae, and in caveolae and clathrin-mediated endocytosis have been documented in cultured cells and tissues. Endocytosis and intracellular degradation of ECM molecules are likely to be major mechanisms that limit the generation and release of bioactive matrix fragments. Certain FN fragments have been identified in vivo, especially in areas of inflammation. FN fragments have been shown to regulate angiogenesis, cell migration, cell proliferation, and chemotaxis. It is not known whether changes in FN endocytosis occur during aging, or whether these changes result in the accumulation of FN fragments. In this application, we will test the novel hypothesis that age-related changes in FN polymerization and/or turnover impair angiogenesis by altering the composition of the ECM and the presence of bioactive ECM fragments that regulate angiogenesis. We will test this hypothesis by: 1) determining whether downregulation of FN endocytosis during aging leads to increased extracellular FN degradation and accumulation of FN fragments; and 2) determining whether altered ECM remodeling during aging leads to impaired angiogenesis. These studies will provide insight into the basic mechanisms that underlie the alterations in ECM that occur during aging, and could lead to the identification of novel targets that could ameliorate some of the consequences of age-related changes in ECM. PUBLIC HEALTH RELEVANCE: There is a progressive decline in the function of most organs and tissues during aging. Aging is also associated with a number of diseases, including arthritis, atherosclerosis, stroke and dementias. We are interested in defining the underlying causes for the decline in cell and tissue function with aging. These studies will provide insight into the basic mechanisms that underlie the alterations in tissues that occur during aging, and could lead to the identification of novel targets that could ameliorate some of the consequences of age-related changes in tissue structure and function.

描述（由申请人提供）：在衰老过程中，大多数器官和组织的功能逐渐下降。衰老还与许多疾病有关，包括关节炎、痴呆、心力衰竭、高血压和动脉粥样硬化。细胞外基质（ECM）的合成、沉积、周转和生物力学特性的与血管生成相关的变化已有充分的文献记载。ECM控制细胞行为的许多方面，包括细胞迁移、增殖、分化和存活，并且在维持正常组织功能和组织修复中起关键作用。因此，ECM和ECM重塑的年龄相关变化可能是血管生成和组织修复的年龄相关下降的主要原因。我们的数据表明，ECM蛋白，纤连蛋白（FN），调节其他ECM分子，包括胶原蛋白I，胶原蛋白III，血小板反应蛋白，和硫酸肝素蛋白多糖的沉积和营业额。此外，调节FN聚合成ECM的因子调节FN和胶原I基质原纤维的稳定性和周转。FN的合成和沉积与年龄有关。由于FN是细胞迁移、细胞增殖、组织机械特性和ECM组成和稳定性的关键调节剂，因此FN代谢中的年龄相关改变可能是细胞和组织功能中年龄相关变化的主要贡献者。我们的数据表明，FN基质周转发生通过内吞作用和细胞内降解，并调节小窝蛋白-1和21整合素。在培养的细胞和组织中，已经记录了细胞膜小窝以及细胞膜小窝和网格蛋白介导的内吞作用的减少。ECM分子的内吞作用和细胞内降解可能是限制生物活性基质片段产生和释放的主要机制。某些FN片段已在体内被鉴定，特别是在炎症区域。FN片段已显示出调节血管生成、细胞迁移、细胞增殖和趋化性。目前尚不清楚衰老过程中是否发生FN内吞作用的变化，或者这些变化是否导致FN片段的积累。在本申请中，我们将测试新的假设，即年龄相关的变化FN聚合和/或营业额损害血管生成，通过改变ECM的组成和生物活性ECM片段，调节血管生成的存在。我们将通过以下方式检验这一假设：1）确定衰老过程中FN内吞作用的下调是否导致细胞外FN降解和FN片段积累增加; 2）确定衰老过程中ECM重塑的改变是否导致血管生成受损。这些研究将深入了解衰老过程中ECM改变的基本机制，并可能导致识别新的靶点，从而改善ECM中与年龄相关的变化的一些后果。公共卫生相关性：在衰老过程中，大多数器官和组织的功能都会逐渐下降。衰老还与许多疾病有关，包括关节炎、动脉粥样硬化、中风和痴呆。我们感兴趣的是确定细胞和组织功能随着衰老而下降的根本原因。这些研究将深入了解衰老过程中发生的组织变化的基本机制，并可能导致识别新的靶点，这些靶点可以改善组织结构和功能中与年龄相关的变化的一些后果。