The HDL receptor, scavenger receptor class B type I (SR-BI), mediates cellular delivery of HDL cholesterol by selective lipid uptake, a mechanism distinct from classic receptor-mediated endocytosis. In addition, SR-BI can bind LDL and VLDL and can mediate both cellular uptake of non-lipoprotein cholesterol and stimulate cellular cholesterol efflux. Using in vivo studies with mice, we have shown that SR-BI plays a key role 1) in determining the structure of HDL and levels of both plasma HDL and biliary cholesterol, 2) in mediating the regulated delivery of HDL-cholesterol to steroidogenic tissues and the liver, and 3) in protecting against atherosclerosis. On a chow-fed apoE knockout (KO) genetic background (standard murine model of spontaneous atherosclerosis), homozygous null mutations in the SR-BI gene (SR-BI KO) cause dramatically accelerated atherosclerosis. In addition, these double KO mice ('dKO') express multiple characteristics commonly seen in human fatal coronary heart disease (CHD) and heart failure, including hypercholesterolemia, occlusive atherosclerosis, myocardial infarction (Ml), cardiac dysfunction and hypertrophy, pump failure and premature death (5-8 weeks of age, 50% mortality at 6 weeks). Crossing various transgenes or targeted gene deletions into dKO mice or treating them with pharmacologic agents is helping to elucidate the mechanisms underlying CHD and has provided additional evidence that this system may serve as a powerful model for human CHD. By crossing SR-BI single KO mice with mice carrying a hypomorphic apoE allele (ApoeR61-h/h), we generated SR-BI KO/ApoeR61-h/h mice that appear normal when fed a chow diet, but when fed an atherogenic ('Paigen') diet develop fatal occlusive CHD that is virtually identical to that in chow-fed dKO mice (50% mortality 32+/-6 days after initiation of the atherogenic diet). Withdrawal of the atherogenic diet can be used to study regression/recovery of disease (atherosclerosis, Ml, heart failure). Analysis of these two murine models of CHD should provide new mechanistic insights and a platform for preliminary analysis of new treatment or prevention strategies. The twin goals of this Project are I) to characterize the mechanisms underlying early onset CHD and death in dKO and SR-BI KO/ApoeR61-h/h mice and assess and improve the validity of these mice as models for human CHD, and II) to use somatic cell genetics to identify at the cellular level the gene products and functions that are required for SR-BI activity and underlie SR-BI's profound effects on the cardiovascular system. A wide array of molecular, cellular, physiologic, imaging, genetic, genomic and pharmacologic approaches will be used in close conjunction with the other Projects and Cores. For example, 1) with the Murine Genetics and Physiology Core we will continue to develop a system called HERMES to acquire, web broadcast and analyze in real time continuous EGG measurements from the very young (and thus small) dKO mice, which will allow us to correlate cardiac function with biochemistry, gene (including microRNA) expression and cardiac morphology. We will collaborate 2) with Projects II and V to evaluate the roles of adhesion molecules, platelets and hemostasis, and inflammation on CHD, 3) with Project III to explore the role of the key energy metabolism hormone adiponectin on CHD, and 4) with Project III in using retroviral technologies and somatic cell genetics to identify cellular genes required for SR-BI activity. As we identify additional genes by somatic cell genetics that are potentially significant contributors to cardiovascular pathophysiology, we will assess the contributions of genetic variation in these genes to clinical phenotypes. We will test the hypotheses that 1) our current and genetically improved SR-BI-based murine systems are valid models for human CHD and can be used to elucidate mechanisms underlying disease, and 2) identification of genes required for SR-BI function in cultured cells will help uncover both SR-BI-specific and globally important mechanisms of membrane protein processing and function. The proposed work should help elucidate key biological mechanisms underlying cardiovascular function and pathophysiology.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts Institute of Technology
United States
Zip Code
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

Showing the most recent 10 out of 118 publications