High-density lipoproteins (HDL, or Good Cholesterol) are heterogeneous nanoparticles that remove cell cholesterol via a complex process termed reverse cholesterol transport (RTC). HDL protect against cardiovascular disease, inflammation, stroke and other major diseases. Understanding distinct functional properties of HDL subclasses and their remodeling during RCT is necessary to improve HDL quality, and is the current thrust in search for novel diagnostic tools and therapies to complement statins, fibrates and other lipid-lowering drugs. Our work will provide the molecular basis necessary for this effort. Our long-term goal is to elucidate the energetics-structure-function relationship in lipopo- teins to better understand and control the molecular mechanisms of lipid transport. This project is focused on the structural stability and functional remodeling of plasma HDL and their main protein, apoA-I. ApoA-I forms a structural scaffold on HDL and directs HDL metabolism by activating plasma factors. ApoA-I destabilization can cause amyloidosis.
In Aim 1, we will test the new structure-based mechanism of apoA-I adaptation to the increasing lipid load in HDL during cholesterol transport. We will use an integrated approach combining established biophysical and biochemical methods with innovative techniques such as field-cycling NMR to characterize HDL surface dynamics. This will be complemented by Aim 2: functional studies of cell cholesterol efflux to lipid-poor apoA-I and to nascent HDL at the critical early steps of RCT.
Aim 3 will test the new structure- based mechanism of apoA-I destabilization and misfolding in systemic amyloidosis. Our studies will provide a structural and dynamic framework necessary for understanding functions of over 60 HDL-associated proteins in health and disease, guide the search for HDL with improved properties for future use as diagnostic markers and personalized HDL-based therapies for cardiovascular disease, and help identify therapeutic targets for apoA-I amyloidosis, a devastating disease for which there is no treatment.

Public Health Relevance

This research will determine how the protein constituents of high-density lipoprotein (a. k. a. Good Cholesterol) adapt to the increasing lipid load during cholesterol removal from the body. This research will also help deter- mine how to block the pathogenic misfolding of these proteins. The results will help find therapeutic targets and design new therapies for major human diseases, including atherosclerosis, diabetes and amyloidosis.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM067260-12
Application #
8725177
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Smith, Ward
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Boston University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02118
Cavigiolio, Giorgio; Jayaraman, Shobini (2014) Proteolysis of apolipoprotein A-I by secretory phospholipase A?: a new link between inflammation and atherosclerosis. J Biol Chem 289:10011-23
Das, Madhurima; Mei, Xiaohu; Jayaraman, Shobini et al. (2014) Amyloidogenic mutations in human apolipoprotein A-I are not necessarily destabilizing - a common mechanism of apolipoprotein A-I misfolding in familial amyloidosis and atherosclerosis. FEBS J 281:2525-42
Gursky, Olga (2014) Hot spots in apolipoprotein A-II misfolding and amyloidosis in mice and men. FEBS Lett 588:845-50
Gursky, Olga (2013) Crystal structure of ýý(185-243)ApoA-I suggests a mechanistic framework for the protein adaptation to the changing lipid load in good cholesterol: from flatland to sphereland via double belt, belt buckle, double hairpin and trefoil/tetrafoil. J Mol Biol 425:1-16
Gursky, Olga; Jones, Martin K; Mei, Xiaohu et al. (2013) Structural basis for distinct functions of the naturally occurring Cys mutants of human apolipoprotein A-I. J Lipid Res 54:3244-57
Meyers, Nathan L; Wang, Libo; Gursky, Olga et al. (2013) Changes in helical content or net charge of apolipoprotein C-I alter its affinity for lipid/water interfaces. J Lipid Res 54:1927-38
Gursky, Olga; Mei, Xiaohu; Atkinson, David (2012) The crystal structure of the C-terminal truncated apolipoprotein A-I sheds new light on amyloid formation by the N-terminal fragment. Biochemistry 51:10-8
Jayaraman, Shobini; Cavigiolio, Giorgio; Gursky, Olga (2012) Folded functional lipid-poor apolipoprotein A-I obtained by heating of high-density lipoproteins: relevance to high-density lipoprotein biogenesis. Biochem J 442:703-12
Jayaraman, Shobini; Abe-Dohmae, Sumiko; Yokoyama, Shinji et al. (2011) Impact of self-association on function of apolipoprotein A-I. J Biol Chem 286:35610-23
Jayaraman, Shobini; Gantz, Donald L; Gursky, Olga (2011) Effects of phospholipase A(2) and its products on structural stability of human LDL: relevance to formation of LDL-derived lipid droplets. J Lipid Res 52:549-57

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