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.
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.
|Shi, Feng; Sottile, Jane (2011) MT1-MMP regulates the turnover and endocytosis of extracellular matrix fibronectin. J Cell Sci 124:4039-50|
|Shi, Feng; Harman, Jennifer; Fujiwara, Keigi et al. (2010) Collagen I matrix turnover is regulated by fibronectin polymerization. Am J Physiol Cell Physiol 298:C1265-75|