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Asymmetric Distribution of Cholesterol in Membranes

膜中胆固醇的不对称分布

基本信息

批准号：
7417159
负责人：
Friedhelm Schroeder
金额：
$ 4.73万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-10-01 至 2009-08-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7417159
关键词：
Address Antibodies Bacterial Toxins Binding Caveolae Caveolins Cell membrane Cell physiology Cells Cholesterol Coupling Data Electron Microscopy Fibroblasts Figs - dietary Gene Targeting Genes Hepatocyte High Density Lipoprotein Cholesterol High Density Lipoproteins Image In Vitro Intervention L Cells Laboratories Laser Scanning Microscopy Lateral Life Localized Mediating Membrane Membrane Lipids Membrane Microdomains Metabolic Diseases Modeling Mus Normal Cell P-Glycoprotein P-Glycoproteins Parasites Permeability Plants Preparation Protein Overexpression Proteins Proteomics Publications Regulation Role Signal Transduction Sterols Structure Time Toxin Variant Virus Yeasts caveolin 1 cell fixing cholesterol trafficking cholesterol-binding protein crosslink immune function in vivo insight interest membrane model non-specific lipid transfer protein pathogen receptor research study reverse cholesterol transport transcytosis uptake yeast two hybrid system

项目摘要

Plasma membrane cholesterol-rich microdomains, lipid rafts and caveolae, mediate HDL reverse cholesterol transport, signaling, antibody recognition, and serve as entry portals for potential bioterror toxins, viruses, and parasites. While cholesterol is essential for lipid raft/caveolae function, almost nothing is known regarding distribution, structure, and regulation of cholesterol in lipid rafts or caveolae. Preliminary Data show sterol carrier protein-2 (SCP-2) binds caveolin-1 in vitro and in vivo, alters lipid raft/caveolae cholesterol domains, and inhibits HDL-mediated cholesterol efflux from cells rich in caveolin-1 (L-cell fibroblasts). In contrast, cultured primary hepatocytes (from wild-type, SCP-2 overexpressing, and SCP-2 gene targeted mice) provide a model for addressing cholesterol membrane dynamics in cells essentially deficient in caveolin-1, but rich in proteins that mediate cholesterol transport between plasma membrane and HDL (SRB1, P-gp, ABCA1). We now propose four specific aims. Aim 1. Determine which proteins (SRB1, ABCA1, P-gp) mediating HDL-cholesterol efflux/uptake are present in plasma membrane lipid rafts versus caveolae, interactions between them, and interactions with caveolin-1. Aim 2. Examine how SCP-2 interacts with caveolin-1, and whether SCP-2 binds lipid raft or caveolae proteins mediating HDL-cholesterol uptake/efflux (SRB 1, ABCA1, P-gp). Aim 3. Resolve if SCP-2 expression alters cholesterol distribution, cholesterol dynamics, and structure in purified rafts and caveolae. SCP-2 level will be modified with SCP-2 overexpressing L-cell fibroblasts and primary cultured hepatocytes from SCP-2 overexpressed and gene-ablated mice. Aim 4. In living cells, determine if SCP-2 expression alters cholesterol distribution, structure, and dynamics in lipid rafts or caveolae. Results will provide fundamental, mechanistic details of cholesterol organization and dynamics in lipid rafts, regulation by SCP-2, differential roles of rafts versus caveolae in mediating HDL-cholesterol uptake/efflux, and insights on potential intervention in metabolic disease, pathogen entry, and bioterror agents.

质膜富含胆固醇的微结构域、脂筏和小泡介导HDL逆转胆固醇