Extracellular Matrix Remodeling During Aging

描述（由申请人提供）：随着年龄的增长，大多数器官和组织的功能会逐渐下降。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、转换和生物力学特性与年龄相关的变化有很好的记录。ECM控制着细胞迁移、增殖、分化和存活等多方面的细胞行为，在维持正常组织功能和组织修复中起着至关重要的作用。因此，与年龄相关的ECM变化和ECM重塑可能是与年龄相关的血管生成和组织修复下降的主要原因。我们的数据表明，ECM蛋白纤维连接蛋白（FN）调节其他ECM分子的沉积和周转，包括胶原I、胶原III、血栓反应蛋白和硫酸肝素蛋白聚糖。此外，调节FN聚合成ECM的因子调节FN和I型胶原基质原纤维的稳定性和周转。FN的合成和沉积与年龄相关。由于FN是细胞迁移、细胞增殖、组织机械特性以及ECM组成和稳定性的关键调节因子，因此与年龄相关的FN代谢改变可能是与年龄相关的细胞和组织功能变化的主要因素。我们的数据显示FN基质的更新是通过胞吞作用和细胞内降解发生的，并由caveolin-1和21整合素共同调节。在培养的细胞和组织中，年龄相关的小泡、小泡和网格蛋白介导的内吞作用减少已被证实。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片段已在体内被发现，特别是在炎症区域。FN片段已被证明可调节血管生成、细胞迁移、细胞增殖和趋化性。目前尚不清楚是否在衰老过程中发生了FN内吞作用的变化，或者这些变化是否导致了FN片段的积累。在这个应用中，我们将验证一个新的假设，即年龄相关的FN聚合和/或周转的变化会通过改变ECM的组成和调节血管生成的生物活性ECM片段的存在来损害血管生成。我们将通过以下方法来验证这一假设：1)确定衰老过程中FN胞吞作用的下调是否会导致细胞外FN降解和FN片段积累增加；2)确定衰老过程中ECM重塑的改变是否会导致血管生成受损。这些研究将深入了解在衰老过程中发生的ECM变化的基本机制，并可能导致发现新的靶点，从而改善与年龄相关的ECM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年龄增长而下降的潜在原因。这些研究将深入了解组织在衰老过程中发生变化的基本机制，并可能导致发现新的靶点，从而改善与年龄相关的组织结构和功能变化的一些后果。

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.