Biology and Pathologies of Type V Collagen

University Of Wisconsin-Madison, Madison WI

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Abstract

This proposal comprises proposed studies into the nature of collagen V and its roles in human disease: 1) Mice homozygous null for the Col5a3 gene, encoding the poorly characterized a3(V) collagen chain, have been produced in the PI[unreadable]s lab. They are viable and fertile, but have a high degree of exercise intolerance, reduced type I collagen fibril diameter in tendons, and overly compliant great vessels of the heart. There is also a gender-specific defect in adipose tissue biology, with markedly decreased adiposity in females, accompanied by decreased serum adipokine levels. Proposed are extensive ultrastructural, mechanical and metabolic characterizations of the [unreadable]phenomics[unreadable] of these mice, towards determining the full range of roles(s) of the a3(V) collagen chain in homeostasis and development, and identifying possible heritable diseases and/or predispositions to chronic ailments in the general human population, due to defects in the human a3(V) gene, COL5A3. 2) We have found autoimmunity to the a1(V) collagen chain to predispose patients to obliterative bronchiolitis(OB), the chronic fibroproliferative process responsible for rejection of >50% of lung transplants. The observation that a1(V) chains are specifically induced in atherosclerotic plaques prompted the PI to hypothesize that a1(V) autoimmunity may also be a component of atherosclerosis. In extraordinary preliminary results, all 4 patients tested thus far with advanced coronary artery disease (CAD) showed collagen V autoimmunity, whereas none of 8 healthy controls showed any evidence ot collagen V autoimmunity; thus strongly supporting the hypothesis (p<0.004). Moreover, the level of autoimmunity in each patient positively correlated with the severity of CAD, as reflected in the number of coronary artery bypass graphs required. The PI proposes, and these results certainly merit, a substantial study to investigate the role of collagen V autoimmunity in atherosclerosis, with patient stratification to determine the possibility of correlations between disease severity and levels of autoimmunity. Also proposed is a study to determine whether a common mechanism involving induction of abnormal a1(V)3 homotrimers and subsequent monocyte/macrophagedependent presentation of normally cryptic a1(V) epitopes to Th17 T cells underlies both OB and atherosclerosis. Atherosclerosis is the most prevalent pathologic process leading to cardiovascular disease, including myocardial infarction and stroke - the number-one killers in the western hemisphere.