ABCA1 agonist peptides for therapeutic use

University Of Calif-Lawrenc Berkeley Lab, Berkeley CA

Investigators

Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): High density lipoproteins (HDL) possess beneficial activities that protect against atherosclerosis. The beneficial effects of HDL are related, in part, to its constituent proteins, such as apolipoprotein(apo) A-I and E, that facilitate the antiatherogenic reverse cholesterol transport (RCT) pathway. Stimulation of cellular cholesterol efflux by apoA-I and E constitutes the rate-limiting step in RCT that generates HDL and reverses the macrophage foam-cell phenotype. These events require the ATP-binding cassette transporter A1 (ABCA1). As a result, ABCA1 is clinically relevant and represents an attractive target for therapeutic interventions to combat atherosclerosis. The long-term objectives of these studies seek to define the molecular basis by which apolipoprotein family members interact with membrane transporters such as ABCA1, identifying fundamental principles and forces that govern and direct the RCT process. The information will be translated into therapeutics to combat diseases of aberrant cholesterol homeostasis. Based on comparative analyses of apoA-I and E C-terminal domains, a high-affinity functional-ligand for ABCA1 was created. The proposed studies will utilize a mouse model of human disease to test whether this novel consensus peptide increases plasma HDL concentrations, promotes RCT activity in vivo, and stimulates the regression of atherosclerotic lesions. The research is of broad biological- and clinical-relevance for understanding how HDL proteins remove excess cholesterol from the artery wall. A new class of therapeutics will be developed based on small peptides formulated from HDL proteins. The research is likely to have a high impact on public health, since the therapeutics will be amenable to the widespread treatment of atherosclerosis. [unreadable] [unreadable] [unreadable] [unreadable]