Our overall goal to understand the role of the adipokine adiponectin in vascular function, atherosclerosis,? and coronary heart disease. Adiponectin is produced exclusively by adipocytes and is found at high levels? in the intima surrounding several types of blood vessels. Adiponectin plays a key role in regulating? hepatic and muscle fat and glucose metabolism and also the metabolism and proliferation of vascular? smooth muscle and possibly endothelial cells. We identified several adiponectin orthologs, expressed? mainly by adipocytes that share biological activities and signaling properties with adiponectin; these, like? adiponectin, may regulate metabolism of vascular cells. The identities of the adiponectin signaling? receptors and signal transduction pathways are not known; our and other labs have unequivocally shown? that previously reported, putative signaling receptors for adiponectin do not function in that capacity. We? identified T-cadherin, a GPI- anchored surface protein, as an adiponectin binding protein that is highly and? specifically expressed by cells in the blood vessel intima. Deletion of T-cadherin in mice results in a? decrease in adiponectin in the vasculature and a major increase in the circulation, indicating it is a major? adiponectin receptor. However, additional cell surface receptors are necessary to mediate adiponectin? signaling. We will clone these signaling adiponectin receptors, analyze their structures and functions in? vitro and in vivo, and determine the signal transduction pathways activated in cultured vascular endothelial? and smooth muscle cells by the three isoforms of adiponectin, focusing initially on the AMP- activated? protein kinase, and NF-kB, MAP kinase, and NO pathways. Cells from T-cadherin -/- mice will allow us to? continue to explore the role of this receptor in adiponectin signaling and localization in the vasculature.? Importantly, with Projects I and II we will determine the effects of the various isoforms and orthologs of? adiponectin and of T-cadherin on blood vessel endothelial and smooth muscle cells and on? atherosclerosis and CHD in apoE -/- and SR-BI/apoE double knockout (dKO) mice. Thus, over the? coming five years we hope to elucidate the roles of adiponectin and its principal vascular binding protein,? T-cadherin, in maintaining the normal state of vascular endothelial and smooth muscle cells, and? understand whether and how deletion of either of these proteins leads to atherosclerosis, thrombosis and? CHD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL066105-08
Application #
7647206
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
8
Fiscal Year
2008
Total Cost
$596,865
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Murphy, Patrick A; Butty, Vincent L; Boutz, Paul L et al. (2018) Alternative RNA splicing in the endothelium mediated in part by Rbfox2 regulates the arterial response to low flow. Elife 7:
Alvarez-Dominguez, Juan R; Knoll, Marko; Gromatzky, Austin A et al. (2017) The Super-Enhancer-Derived alncRNA-EC7/Bloodlinc Potentiates Red Blood Cell Development in trans. Cell Rep 19:2503-2514
Alvarez-Dominguez, Juan R; Lodish, Harvey F (2017) Emerging mechanisms of long noncoding RNA function during normal and malignant hematopoiesis. Blood 130:1965-1975
Dockendorff, Chris; Faloon, Patrick W; Germain, Andrew et al. (2015) Discovery of bisamide-heterocycles as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake. Bioorg Med Chem Lett 25:2594-8
Turner, Christopher J; Badu-Nkansah, Kwabena; Crowley, Denise et al. (2015) ?5 and ?v integrins cooperate to regulate vascular smooth muscle and neural crest functions in vivo. Development 142:797-808
Alvarez-Dominguez, Juan R; Bai, Zhiqiang; Xu, Dan et al. (2015) De Novo Reconstruction of Adipose Tissue Transcriptomes Reveals Long Non-coding RNA Regulators of Brown Adipocyte Development. Cell Metab 21:764-776
Dockendorff, Chris; Faloon, Patrick W; Pu, Jun et al. (2015) Benzo-fused lactams from a diversity-oriented synthesis (DOS) library as inhibitors of scavenger receptor BI (SR-BI)-mediated lipid uptake. Bioorg Med Chem Lett 25:2100-5
Murphy, Patrick A; Begum, Shahinoor; Hynes, Richard O (2015) Tumor angiogenesis in the absence of fibronectin or its cognate integrin receptors. PLoS One 10:e0120872
Hu, Wenqian; Yuan, Bingbing; Lodish, Harvey F (2014) Cpeb4-mediated translational regulatory circuitry controls terminal erythroid differentiation. Dev Cell 30:660-72
Alvarez-Dominguez, Juan R; Hu, Wenqian; Gromatzky, Austin A et al. (2014) Long noncoding RNAs during normal and malignant hematopoiesis. Int J Hematol 99:531-41

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