Proposed are studies into the nature of collagen V [col(V)] and its roles in human disease: 1) Mice null for the Col5a3 gene, encoding the poorly characterized 13(V) chain, have been produced in the principal investigator's lab. They are viable and fertile, but have marked exercise intolerance, reduced collagen fibril diameter in tendons, and overly compliant great vessels of the heart. Col5a3 is most highly expressed in adipose tissue, and Col5a3-/- females also have decreased adiposity, accompanied by glucose-intolerance, insulin-resistance, and decreased adipokine levels. Proposed are extensive characterizations of these mice, to determine the full range of 13(V) roles in ultrastructure, cell biology, development, metabolism, homeostasis and disease - the latter including possible heritable diseases and/or predispositions to chronic ailments in the general human population. High 13(V) levels in mammary fat pads and exceptionally high levels of 13(V) juxtaposed to mammary gland ducts, combined with the known importance of collagenous matrix to the etiology of breast carcinoma and the up-regulation of col(V) in desmoplasia, have also prompted proposed studies into effects of 13(V) ablation on pathogenesis of mammary carcinomas. A newer strain of mice with a dominant negative Col5a3 allele has also been created by the principal investigator's lab, and appears to have a more pronounced phenotype than the Col5a3-nulls, providing a model that should facilitate determining the biological roles of the 13(V) chain. 2) We previously found autoimmunity to the 11(V) collagen chain to predispose patients to obliterative bronchiolitis(OB), the fibroproliferative process responsible for rejection of >50% of lung transplants. An observation that 11(V) chains are specifically induced in atherosclerotic plaques prompted the principal investigator to hypothesize that 11(V) autoimmunity may also be a component of atherosclerosis. In extraordinary preliminary results, 11 of 12 coronary artery disease (CAD) patients tested had clear-cut col(V) autoimmunity, whereas none of 10 healthy controls had any evidence of col(V) autoimmunity;thus strongly supporting the hypothesis (p<0.0001). Moreover, the level of autoimmunity in each patient positively correlated with CAD severity, as reflected in the number of bypass graphs required. The principal investigator proposes, and these results certainly merit, a substantial study of the role of col(V) autoimmunity in atherosclerosis, with patient stratification to test for correlations between disease severity and levels of autoimmunity. Also proposed are studies in animal models, to test whether col(V) autioimmunity is causal in the pathogenesis of atherosclerosis, and whether induction of col(V) immune tolerance can ameliorate the morbidity of atherosclerosis. Also proposed are studies to determine whether a common mechanism involving induction of abnormal 11(V)3 homotrimers and subsequent monocyte/macrophage-dependent presentation of 11(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. Public Health Relevance: We've found that damaging a particular gene in mice results in reduced body fat, diabetic symptoms, abnormal major blood vessels of the heart, and marked inability to perform exercise. Analyses of these mice should provide insights not only into how this gene works, but also into which human patients in the general population may suffer form defects in the same gene. We also intend to show that severe atherosclerosis/coronary artery disease is, at least partly, an autoimmune disease directed against one of the body's own proteins. If such studies are borne out, the ramifications are huge, with profound implications for understanding, evaluating and treating atherosclerotic disease - the number one killer of adult human beings in the western hemisphere.
We've found that damaging a particular gene in mice results in reduced body fat, diabetic symptoms, abnormal major blood vessels of the heart, and marked inability to perform exercise. Analyses of these mice should provide insights not only into how this gene works, but also into which human patients in the general population may suffer form defects in the same gene. We also intend to show that severe atherosclerosis/coronary artery disease is, at least partly, an autoimmune disease directed against one of the body's own proteins. If such studies are borne out, the ramifications are huge, with profound implications for understanding, evaluating and treating atherosclerotic disease - the number one killer of adult human beings in the western hemisphere.
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