The mechanical properties of developing and mature organ systems are primarily determined by the deposition of fibrillar collagens in the extracellular matrix. It follows that structural defects in these macromolecules cause dominantly inherited conditions that adversely affect the integrity of bodily organs. In addition to their supportive function, collagens also play a dynamic role in a number of developmental programs and physiological processes, such as tissue remodeling and wound healing. Deregulated collagen biosynthesis is the hallmark of several pathological conditions, including fibrotic, inflammatory and arthritic diseases. It is the long-term goal of this application to elucidate the mechanisms underlying collagen pathophysiology. Toward this end, two major research themes are proposed. The first will explore the phenotypic consequences of collagen mutations in human conditions and in transgenic mice. The second will decipher the molecular circuitries that require collagen biosynthesis. Specifically, we will characterize type II collagen mutations in chondrodysplastic patients to confirm and extend the genetic and clinical understanding of this collagenopathy. We will utilize the transgenic mouse model to establish the function and pathogenesis of minor fibrillar collagen types. We will employ transfection experiments and DNA:protein binding assays to identify cis-acting regulatory elements that control the expression of collagen genes. Finally, we will clone the genes encoding the trans-acting factors that regulate collagen expression. The thrust of this work is to achieve a better understanding of connective tissue pathology as it relates to the function and biosynthesis of fibrillar collagen types.