EXCEED THE SPACE PROVIDED. This propsal comprises studies into the nature of type V collagen and its roles in human disease: 1) Characterization of mice with null alleles for the alpha 3(V) chain gene, Col5a3. Mice homozygdus null for Col5a3 have been produced in the Pi'slab.They are viable and fertile, but have a high degree of exercise intolerance, and aortae and pulmonary arteries (which normallly have high levels of alpha 3(V) chains) that are much more compliant than wild type. Characterization will include immunohistochemical and EM analyses of the distribution of alpha 3(V) chains in wild type veins and arteries, effects of alpha 3(V) ablation on blood pressures in exercising Col5a3-/- mice and Col5a3-/- mice at rest, the nature of structures normally formed by alpha 3(V) chains or into which such chains are incorporated, ultrastructural and biomechanical studies on Col5a3-/- tissues in which alpha 3(V) chains are normally found (e.g.blood vessels, ligaments, tendons, bone, peripheral nerves and adipose tissue). Such studies are planned to provide insights into possible heritable deseases and predispositions to chronic ailments caused by defects in the COL5A3 gene in the general human population. 2) We've established primer sets, PCR/RT-PCR conditions, and polymorphisms that allow testing for mutations throughout the entire COL5A3 coding region and for loss of heterozygosity of expressed sequences (null alleles). We've recently used these to exclude COL5A3 as a candidate for the hypermobility form of Ehlers-Danlos syndrome (EDS), and propose using these resources to analyse other patients with phenotypes that resemble phenotypic attributes uncovered in the Col5a3 knockout mice. We would begin such studies on cases of classical EDS (and EDS cases which do not clearly fit into one of the formal clinical subgroups) in which COL5A1, COL5A2 and the major fibrillar collagen genes have been excluded. 3) We have found autoimmune responses against the alpha 1 (V) chain to be strongly associated with the onset of severe bronchiolitis obliterans syndrome, the leading cause of chronic rejection of transplanted lungs in humans. We propose determining whether autoimmunity against type V collagen is associated with the inflamation and immune responses attending atherogenesis. This latter aim is in part prompted by the observation that alpha 1(V) chains are specifically upregulated in atherosclerotic plaques. PERFORMANCE SITE ========================================Section End===========================================
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