Genomes and Genes
Biology and Pathologies of Type V Collagen
Principal Investigator: Daniel S Greenspan
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 1992-07-01 - 2014-06-30
more information: NIH RePORT
- IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplantsWilliam J Burlingham
Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA
J Clin Invest 117:3498-506. 2007..These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration...
- Comprehensive mass spectrometric mapping of the hydroxylated amino acid residues of the α1(V) collagen chainChenxi Yang
Department of Chemistry, University of Wisconsin, Madison, WI 53706, USA
J Biol Chem 287:40598-610. 2012..1(V) is an extensively modified collagen chain important in disease...
- Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafishP V AshaRani
Institute of Molecular and Cell Biology, Proteos, Singapore, Singapore
Am J Hum Genet 90:661-74. 2012..We thus define the molecular and cellular bases of BMP1-dependent osteogenesis and show the importance of this protein for bone formation and stability...
- ECM roles in the function of metabolic tissuesGuorui Huang
Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53792, USA
Trends Endocrinol Metab 23:16-22. 2012..This review summarizes data that provide insights into the roles of the ECM in informing the proper development and functioning of highly specialized cells of metabolic tissues, such as adipocytes and islet β cells...
- Metalloproteinases in Drosophila to humans that are central players in developmental processesAlison Muir
Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA
J Biol Chem 286:41905-11. 2011....
- Bone morphogenetic protein-1 processes insulin-like growth factor-binding protein 3Byoungjae Kim
Department of Cell and Regenerative Biology, University of Wisconsin, Madison, Wisconsin 53706, USA
J Biol Chem 286:29014-25. 2011..Similarly, in zebrafish embryos, overexpression of Bmp1a is shown to reverse an Igfbp3-induced phenotype, consistent with the ability of BMP1-like proteinases to cleave IGFBP3 in vivo...
- α3(V) collagen is critical for glucose homeostasis in mice due to effects in pancreatic islets and peripheral tissuesGuorui Huang
Department of Cell and Regenerative Biology, University of Wisconsin, Madison, Wisconsin 53706, USA
J Clin Invest 121:769-83. 2011..Our results underscore the emerging view of the importance of ECM to the microenvironments that inform proper development/functioning of specialized cells, such as adipocytes, β cells, and skeletal muscle...
- Interleukin-17-dependent autoimmunity to collagen type V in atherosclerosisMelanie L Dart
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, 1300 University Ave, Madison, WI 53706, USA
Circ Res 107:1106-16. 2010..Because specific induction of α1(V) chains has previously been reported in human atheromas, we postulated involvement of col(V) autoimmunity in atherosclerosis...
- Characterization of the six zebrafish clade B fibrillar procollagen genes, with evidence for evolutionarily conserved alternative splicing within the pro-alpha1(V) C-propeptideGuy G Hoffman
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA
Matrix Biol 29:261-75. 2010..Data presented herein provide insights into the nature of clade B procollagen chains and should facilitate their study in the zebrafish model system...
- Th-17, monokines, collagen type V, and primary graft dysfunction in lung transplantationJoseph L Bobadilla
Microbiology and Immunology, Director, Center for Immunobiology, Indiana University School of Medicine, Van Nuys Medical Sciences Building MS224, 635 Barnhill Drive, Indianapolis, IN 46202 5120, USA
Am J Respir Crit Care Med 177:660-8. 2008..Human studies and rodent models have shown that collagen type V (col[V]), stimulates IL-17-dependent cellular immunity after lung transplantation...
- IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitisRagini Vittal
Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Am J Physiol Lung Cell Mol Physiol 304:L401-14. 2013..Our findings highlight a feed-forward loop between IL-17 and TGF-β, leading to induction of col(V) and associated epithelial repair, thus providing one possible link between autoimmunity and OB after lung transplantation...
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