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)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
4R01GM067260-14
Application #
9094618
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Smith, Ward
Project Start
1998-12-15
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
14
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Boston University
Department
Physiology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
Wilson, Christopher J; Das, Madhurima; Jayaraman, Shobini et al. (2018) Effects of Disease-Causing Mutations on the Conformation of Human Apolipoprotein A-I in Model Lipoproteins. Biochemistry 57:4583-4596
Klimtchuk, Elena S; Prokaeva, Tatiana; Frame, Nicholas M et al. (2018) Unusual duplication mutation in a surface loop of human transthyretin leads to an aggressive drug-resistant amyloid disease. Proc Natl Acad Sci U S A 115:E6428-E6436
Jayaraman, Shobini; Gantz, Donald L; Haupt, Christian et al. (2018) Serum amyloid A sequesters diverse phospholipids and their hydrolytic products, hampering fibril formation and proteolysis in a lipid-dependent manner. Chem Commun (Camb) 54:3532-3535
Jayaraman, Shobini; Sánchez-Quesada, Jose Luis; Gursky, Olga (2017) Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: Potential implications for treatment of apolipoprotein deposition diseases. Biochim Biophys Acta Mol Basis Dis 1863:200-210
Jayaraman, Shobini; Gantz, Donald L; Haupt, Christian et al. (2017) Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis. Proc Natl Acad Sci U S A 114:E6507-E6515
Frame, Nicholas M; Jayaraman, Shobini; Gantz, Donald L et al. (2017) Serum amyloid A self-assembles with phospholipids to form stable protein-rich nanoparticles with a distinct structure: A hypothetical function of SAA as a ""molecular mop"" in immune response. J Struct Biol 200:293-302
Madico, Guillermo; Gursky, Olga; Fairman, Jeff et al. (2017) Structural and Immunological Characterization of Novel Recombinant MOMP-Based Chlamydial Antigens. Vaccines (Basel) 6:
Prokaeva, Tatiana; Akar, Harun; Spencer, Brian et al. (2017) Hereditary Renal Amyloidosis Associated With a Novel Apolipoprotein A-II Variant. Kidney Int Rep 2:1223-1232
Klimtchuk, Elena S; Prokaeva, Tatiana B; Spencer, Brian H et al. (2017) In vitro co-expression of human amyloidogenic immunoglobulin light and heavy chain proteins: a relevant cell-based model of AL amyloidosis. Amyloid 24:115-122
Frame, Nicholas M; Gursky, Olga (2017) Structure of serum amyloid A suggests a mechanism for selective lipoprotein binding and functions: SAA as a hub in macromolecular interaction networks. Amyloid 24:13-14

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