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.

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047746-17
Application #
8289365
Study Section
Intercellular Interactions (ICI)
Program Officer
Tseng, Hung H
Project Start
1992-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
17
Fiscal Year
2012
Total Cost
$314,234
Indirect Cost
$100,394
Name
University of Wisconsin Madison
Department
Pathology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Vittal, Ragini; Fan, Lin; Greenspan, Daniel S et al. (2013) IL-17 induces type V collagen overexpression and EMT via TGF-ýý-dependent pathways in obliterative bronchiolitis. Am J Physiol Lung Cell Mol Physiol 304:L401-14
Asharani, P V; Keupp, Katharina; Semler, Oliver et al. (2012) Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. Am J Hum Genet 90:661-74
Huang, Guorui; Greenspan, Daniel S (2012) ECM roles in the function of metabolic tissues. Trends Endocrinol Metab 23:16-22
Huang, Guorui; Ge, Gaoxiang; Wang, Dingyan et al. (2011) ýý3(V) collagen is critical for glucose homeostasis in mice due to effects in pancreatic islets and peripheral tissues. J Clin Invest 121:769-83
Dart, Melanie L; Jankowska-Gan, Ewa; Huang, Guorui et al. (2010) Interleukin-17-dependent autoimmunity to collagen type V in atherosclerosis. Circ Res 107:1106-16
Bobadilla, Joseph L; Love, Robert B; Jankowska-Gan, Ewa et al. (2008) Th-17, monokines, collagen type V, and primary graft dysfunction in lung transplantation. Am J Respir Crit Care Med 177:660-8
Burlingham, William J; Love, Robert B; Jankowska-Gan, Ewa et al. (2007) IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest 117:3498-506
Jasuja, Reema; Ge, Gaoxiang; Voss, Nikolas G et al. (2007) Bone morphogenetic protein 1 prodomain specifically binds and regulates signaling by bone morphogenetic proteins 2 and 4. J Biol Chem 282:9053-62
Zhang, Yue; Ge, Gaoxiang; Greenspan, Daniel S (2006) Inhibition of bone morphogenetic protein 1 by native and altered forms of alpha2-macroglobulin. J Biol Chem 281:39096-104
Ge, Gaoxiang; Greenspan, Daniel S (2006) Developmental roles of the BMP1/TLD metalloproteinases. Birth Defects Res C Embryo Today 78:47-68

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