Extracellular Matrix Remodeling During Aging

描述(申请人提供)：在衰老过程中，大多数器官和组织的功能会逐渐衰退。衰老还与许多疾病有关，包括关节炎、痴呆症、心力衰竭、高血压和动脉粥样硬化。随着年龄的增长，细胞外基质(ECM)的合成、沉积、周转和生物力学性质的变化被很好地记录下来。细胞外基质控制着细胞的迁移、增殖、分化和存活等多个方面的行为，在维持正常组织功能和组织修复中起着关键作用。因此，与年龄相关的ECM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。我们的数据显示，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I型胶原、III型胶原、凝血酶敏感蛋白和硫酸肝素蛋白多糖。此外，调节FN聚合成ECM的因素调节FN和I型胶原基质纤维的稳定性和周转。FN的合成和沉积随年龄增长而增加。由于FN是细胞迁移、细胞增殖、组织力学性质、ECM组成和稳定性的关键调节因子，FN代谢的年龄相关改变可能是细胞和组织功能的年龄相关变化的主要贡献因素。我们的数据表明，FN基质的周转通过内吞和细胞内降解发生，并受小窝蛋白-1和21整合素的调节。在培养的细胞和组织中，与年龄相关的小窝减少，小窝和网状蛋白介导的内吞作用也被记录下来。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。已经在体内发现了某些FN片段，特别是在炎症区域。FN片段已被证明调节血管生成、细胞迁移、细胞增殖和趋化作用。目前尚不清楚FN内吞作用的变化是否发生在衰老过程中，或者这些变化是否导致FN片段的积累。在这一应用中，我们将检验这一新的假设，即FN聚合和/或周转的年龄相关变化通过改变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。我们将通过以下两个方面验证这一假设：1)确定衰老过程中FN内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细胞外基质发生变化的基本机制，并可能导致识别新的靶点，从而改善与年龄相关的细胞外基质变化的一些后果。与公共卫生相关：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、中风和痴呆症。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。这些研究将提供对衰老过程中发生的组织变化的基本机制的洞察，并可能导致识别新的靶点，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.