We seek to elucidate how collagen molecules participate in the assembly of higher order tissue structure and implicitly, how collagen dysfunctions contribute to the genesis and progression of connective tissue disorders. Collagens are the most abundant and diverse components of the connective tissue and thus, the major structural determinants of organ formation and function. Stage and tissue-specific interactions among collagens, other matrix components, surrounding cells and signaling molecules are responsible for the variety of forms and functions of the developing and mature connective tissue. In spite of much progress, there is still a significant gap in our understanding of the mechanisms that translate the structural and cellular interactions of collagen molecules into the physiological properties of connective tissues. The lack of this basic science information in turn hampers our ability to model effective new therapies for a variety of human diseases in which organ function is severely or irreversibly impaired. Based on past discoveries and exciting new data, we hypothesize that timely deposition of collagen XIX in selected basement membrane zones (BMZ) specifies their organization and instructs tissue differentiation. BMZ are morphologically defined entities that consist of BM scaffolds interposed between the cells and interstitial matrices. BMZ play both structural and instructive role in tissue formation, maintenance and remodeling. Mutations in BMZ-associated collagens result in clinical manifestations as diverse as skin blistering, cardiovascular dysfunctions, ocular degeneration, kidney failure, hemorrhagic stroke, and muscle degeneration. In contrast to the cell-BM interface, information about the molecular interconnections between the BM and the underlying stroma is still primitive. Our genetic studies in mice have recently implicated collagen XIX as a potential new component of the molecular network that organizes the architecture of specialized BMZ. They have also suggested that assembly of a collagen XlX-rich matrix promotes cell differentiation. It is the main objective of the present application to fully characterize the role of collagen XIX in organ physiology, as the means to advance knowledge of the mechanisms that specify tissue architectures and functions. We therefore propose to characterize the structural and instructive roles of collagen XIX by studying the structural properties and molecular interactions that contribute to BMZ assembly and function, and tissue differentiation and growth. Clinical relevance: The proposed studies will generate new basic science information that will improve our understanding of the genesis and progression of connective tissue disorders, with potential benefits to the clinical management and therapy of many of these debilitating and often lethal conditions. ? ? ?
Showing the most recent 10 out of 71 publications
