Molecular Dynamics & Regulation of Apo A-I's Conformation

Institution:	Children's Hospital Oakland Research Institute
Investigator(s):	Michael Oda, Ph.D.
Award Cycle:	2007 (Cycle 16)	Grant #: 16RT-0163	Award: $644,293
Subject Area:	Cardiovascular Disease
Award Type:	Research Project Awards

Abstracts

Initial Award Abstract

There is a strong positive correlation between chronic exposure to tobacco smoke and an increased incidence of atherosclerosis and its clinical sequelae: coronary artery disease, peripheral vascular disease, and stroke. In fact, atherosclerosis is one of the primary causes of death amongst tobacco smokers. Conversely, high density lipoprotein (HDL) is correlated with a reduced risk for atherosclerosis. This is due in large part to HDL's ability to remove cholesterol from atherosclerotic plaques and deliver it to the liver for excretion through the bile. Apolipoprotein A-I (apoA-I) is the primary protein component of HDL and as such is a principal determinant of HDL's biological activity. ApoA-I is a member of the exchangeable lipoprotein class of proteins which possess the unique ability to freely transition between lipid and aqueous environments while maintaining their solubility. This adaptability is facilitated by a global conformational rearrangement of the molecule as it transitions between environments. This ability is critical to the mobilization of cholesterol out of atherosclerotic plaques by HDL but is poorly understood. In this proposed study we will examine the manner in which apoA-I regulates and facilitates this structural response to changes in its environment, and how oxidative conditions that arise from the tobacco smoke induced state of chronic inflammation influence HDL's ability to reverse the onset of atherosclerosis. From this information we will gain a greater understanding of the molecular processes which govern HDL's ability to reverse one of the major effects of smoking, namely the formation and progression of the atherosclerotic plaque and how oxidation interferes with this process. Such knowledge will establish the foundation for structure-based drug design, stemming from a better mechanistic understanding of the manner in which apoA-I and other exchangeable apolipoproteins bind and sequester lipid.

Publications

Mapping the structural transition in an amyloidogenic apolipoprotein A-I
Periodical: Biochemistry			Index Medicus:
Authors: Lagerstedt, J.O., Cavigiolio, G., Roberts, L.M., Hong, H.S., Jin, L.W., Fitzgerald, P.G.,				ART
Yr: 2007	Vol: 46	Nbr: 34	Abs:	Pg: 993-9

Myeoperoxidase and inflammatory proteins: pathways for generating dysfunctional high-density lipoprotein in humans
Periodical: Atherosclerosis			Index Medicus:
Authors: Vaisar, T., Shao, B., Green, P.S., Oda, M.N., Oram, J.F., Heinecke, J.W.				ART
Yr: 2007	Vol: 9	Nbr: 5	Abs:	Pg: 417-24

The Interplay between Size, Morphology, Stability, and Functionality of High Density Lipoprotein Subclasses
Periodical: Biochemistry			Index Medicus:
Authors: Cavigiolio, G., Shao, B., Geier, E.G., Henecke, J.W., Oda, M.N.				ART
Yr: 2008	Vol: 47	Nbr:	Abs:	Pg: 4770-9

Myeloperoxidase: an oxidative pathwayfor generating dysfunctional high-density lipoprotein
Periodical: Chemical Research in Toxicology			Index Medicus:
Authors: Shao, B; Oda, MN;				ART
Yr: 2010	Vol: 23	Nbr: 3	Abs:	Pg: 447-454

The exchange of apolipoprotein A-1 between the lipid-associated and the lipid-free states: a potential target for oxidative generation of dysfunctiional HDL.
Periodical: Journal of Biological Chemistry			Index Medicus:
Authors: Cavigiloio,G; Geier, EG; Shao, B; Heinecke, JW; Oda, MN				ART
Yr: 2010	Vol: 285	Nbr: 24	Abs:	Pg: 1884-18857

Myeloid differentation primary response protein 88 couples reverse cholesterol transport to inflammation.
Periodical: Cell Metabolism			Index Medicus:
Authors: Smoak, Jim, Aloor, Madenspacher, Merrick, Collins, Zhu, Cavigiolio, Oda, Parks, Fessler				ART
Yr: 2010	Vol: 11	Nbr: 6	Abs:	Pg: 493-502

A phospholipid-apoliproteinA-1 nanoparticle containing amphotericin B as a drug delivery platform with cell membrane protective properties.
Periodical: International Journal of Pharmacy			Index Medicus:
Authors: Burgess, BL; Cavigiolio, G; Fannucchi, MV; Illek, B; Forte, TM; Oda, MN				ART
Yr: 2010	Vol:	Nbr:	Abs:	Pg:

The morphology and structure of lipoproteins revealed by optimized negative staining.
Periodical: Journal of Lipid Research			Index Medicus:
Authors: Song; Zhang; Cavigolio; Ishida; Zhang; Weisgraber; Pownall; Rye; Kane; Oda; Gang Ren				ART
Yr: 2010	Vol:	Nbr:	Abs:	Pg:

Mapping the structural transition in an amyloidogenic apolipoprotein A-I
Periodical: Biochemistry			Index Medicus:
Authors: Lagerstedt, J.O., Cavigiolio, G., Roberts, L.M., Hong, H.S., Jin, L.W., Fitzgerald, P.G.,				ART
Yr: 2007	Vol: 46	Nbr: 34	Abs:	Pg: 993-9

Myeoperoxidase and inflammatory proteins: pathways for generating dysfunctional high-density lipoprotein in humans
Periodical: Atherosclerosis			Index Medicus:
Authors: Vaisar, T., Shao, B., Green, P.S., Oda, M.N., Oram, J.F., Heinecke, J.W.				ART
Yr: 2007	Vol: 9	Nbr: 5	Abs:	Pg: 417-24

The Interplay between Size, Morphology, Stability, and Functionality of High Density Lipoprotein Subclasses
Periodical: Biochemistry			Index Medicus:
Authors: Cavigiolio, G., Shao, B., Geier, E.G., Henecke, J.W., Oda, M.N.				ART
Yr: 2008	Vol: 47	Nbr:	Abs:	Pg: 4770-9

Myeloperoxidase: an oxidative pathwayfor generating dysfunctional high-density lipoprotein
Periodical: Chemical Research in Toxicology			Index Medicus:
Authors: Shao, B; Oda, MN;				ART
Yr: 2010	Vol: 23	Nbr: 3	Abs:	Pg: 447-454

The exchange of apolipoprotein A-1 between the lipid-associated and the lipid-free states: a potential target for oxidative generation of dysfunctiional HDL.
Periodical: Journal of Biological Chemistry			Index Medicus:
Authors: Cavigiloio,G; Geier, EG; Shao, B; Heinecke, JW; Oda, MN				ART
Yr: 2010	Vol: 285	Nbr: 24	Abs:	Pg: 1884-18857

Myeloid differentation primary response protein 88 couples reverse cholesterol transport to inflammation.
Periodical: Cell Metabolism			Index Medicus:
Authors: Smoak, Jim, Aloor, Madenspacher, Merrick, Collins, Zhu, Cavigiolio, Oda, Parks, Fessler				ART
Yr: 2010	Vol: 11	Nbr: 6	Abs:	Pg: 493-502

A phospholipid-apoliproteinA-1 nanoparticle containing amphotericin B as a drug delivery platform with cell membrane protective properties.
Periodical: International Journal of Pharmacy			Index Medicus:
Authors: Burgess, BL; Cavigiolio, G; Fannucchi, MV; Illek, B; Forte, TM; Oda, MN				ART
Yr: 2010	Vol:	Nbr:	Abs:	Pg:

The morphology and structure of lipoproteins revealed by optimized negative staining.
Periodical: Journal of Lipid Research			Index Medicus:
Authors: Song; Zhang; Cavigolio; Ishida; Zhang; Weisgraber; Pownall; Rye; Kane; Oda; Gang Ren				ART
Yr: 2010	Vol:	Nbr:	Abs:	Pg: