The focus of this application is to determine the mechanisms of tendon extracellular matrix assembly that allow for the independent regulation of initial fibril assembly as well as growth in length and diameter. Assembly of the tendon-specific matrix is a multistep process. Our model is that collagen fibrils are initially assembled as discrete fibril intermediates that are incorporated into fibers within the developing matrix. This is followed by a regulated growth and maturation of fibrils from these preformed intermediates. This involves assembly to form longer (linear growth) and larger diameter (lateral growth) fibrils. The elucidation of the mechanisms regulating these steps is essential to an understanding of normal tendon development.
The Specific Aims of this application are to: (1) define the fibril sub-populations associated with fibrillogenesis and analyze the changes in fibril length during tendon development, (2) characterize the roles of heterotypic type I/III collagen interactions in the regulation of assembly of tendon fibril intermediates; (3) elucidate the roles of decorin, lumican and fibromodulin in the regulation of specific steps in tendon fibrillogenesis; and (4) determine the roles of type XIV collagen in regulation of fibril growth. We will utilize transgenic mice deficient in type III collagen, type XIV collagen, decorin, fibromodulin or lumican with structural, morphometric, molecular, biochemical and immunochemical approaches. One hypothesis is that the heterotypic interaction of fibrillar collagens is a major mechanism regulating the initial assembly of collagen into fibril intermediates. In addition, leucine-rich repeat proteins act at different stages in tendon development to regulate specific steps in fibrillogenesis. Different expression patterns, binding sites and binding affinities mediate these effects. We also hypothesize that type XIV collagen is involved in regulating the transition into and controlled progression through linear growth. These studies will define the mechanisms regulating the steps in tendon-specific matrix assembly during development and lead to potential manipulations during growth, injury and repair, as well as to the understanding of inherited disorders.
Showing the most recent 10 out of 55 publications
