Role of PKCbeta in Diet-induced Hypercholesterolemia

PKCbeta 在饮食引起的高胆固醇血症中的作用

基本信息

批准号：
7326829
负责人：
KAMAL D MEHTA
金额：
$ 28.35万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-06 至 2009-07-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7326829
关键词：
ATP-Binding Cassette Transporters Abbreviations Affect Affinity Aging American Amino Acids Anabolism Animals Apolipoprotein E Apolipoproteins Arts Atherosclerosis Attention Binding Binding Proteins Binding Sites Biochemical Biological Assay Calories Cause of Death Cell physiology Cholesterol Cholesterol Homeostasis Complement Complex Coronary Arteriosclerosis Cyclodextrins Diet Dietary Cholesterol Dietary Fats Doctor of Philosophy Endoplasmic Reticulum Environment Extracellular Signal Regulated Kinases Family Fatty acid glycerol esters Figs - dietary Gene Expression Genes Genetic Goals Golgi Apparatus Hepatic Hepatocyte High Density Lipoproteins Human Hypersensitivity Individual Investigation Knock-out Knowledge LDL Cholesterol Lipoproteins Ligands Link Lipids Lipoproteins Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins MAP Kinase Gene MAPK14 gene MEKKs MEKs Mass Spectrum Analysis Measures Mediating Membrane Mink Mitogen-Activated Protein Kinases Mitogens Mixed Function Oxygenases Modification Molecular Molecular Biology Mus Mutant Strains Mice Nature Phenotype Phosphorylation Phosphotransferases Physiological Physiology Plasma Population Preventive Process Property Protein Binding Protein Isoforms Protein Kinase Protein Kinase C Protein Overexpression Proteins Proteolysis Proteolytic Processing Rate Regulation Regulator Genes Response Elements Risk Factors Role Serum Signal Pathway Signal Transduction Signal Transduction Pathway Societies Squalene Synthetase Sterols Stress Structure Techniques Time Transgenic Mice Transgenic Organisms Twin Studies Work base cholesterol absorption citrate carrier day density dietary excess disability disorder prevention feeding gain of function genetic linkage analysis human MAP3K1 protein hypercholesterolemia i-cholesterol lipid disorder loss of function mutant protein kinase C beta receptor receptor expression response saturated fat sensor site-1 protease tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Coronary artery disease (CAD) remains the leading cause of death and disability in our society. Of all known risk factors promoting CAD, a high serum level of low-density lipoprotein (LDL)-cholesterol is one of the most important risk factors. The plasma level of this lipoprotein is strongly influenced by genetic factors and the amount of dietary fat and cholesterol; dietary modification remains the cornerstone of CAD prevention. Our knowledge of the regulatory mechanism(s) controlling cholesterol homeostasis in response to dietary cholesterol is limited, as is the role of signaling pathways initiated by alterations in cholesterol levels. Also, the interrelationships between these signaling pathways and sterol response element-binding proteins (SREBPs), as well as the mechanism linking SREBP processing and cholesterol levels are not clear. The emerging picture from our work is that regulation of hepatic LDL receptors, crucial for cholesterol homeostasis, results from the activity of a few interlinked regulatory signaling pathways. We have previously shown, for the first-time, involvement of specific isoforms of protein kinase C (PKC) in the regulation of LDL receptor expression in cultured hepatic cells, possibly through direct modulation of activity by cholesterol. Based on our recent results, we propose a central role for B-isoform of PKC (PKCb) in regulating cholesterol homeostasis via modulating expression of selected genes crucial for this process. In Specific Aim 1, the role of PKCb in cholesterol homeostasis will be established by evaluating the effect of knockout of this ldnase on overall cholesterol homeostasis. Initial studies with PKC(-deficient mice strongly support a central role of this kinase in controlling the responsiveness of plasma cholesterol to the changes in the dietary cholesterol content. Cholesterol metabolism will be compared in detail between normal and PKCb mutants fed special diets. The Specific Aim 2 will compare expression of the hepatic genes critical for cholesterol homeostasis in the above animals. In Specific Aim 3, mechanisms by which PKCb affects SREBP-2 expression and its proteolytic processing, possibly by regulating INSIG- 1 phosphorylation will be examined. Finally, the nature of the isoform-specific interaction between cholesterol and PKCb will be examined in the Specific Aim 4. The photoactive cholesterol probe will be used to define at the molecular level structure(s) and amino acids that produce isoform-specific binding of PKCb to cholesterol. The proposed studies will not only establish the role of PKCb in diet-induced hypercholesterolemia, but will also identify genes regulated by this kinase, to correlate regulatory mechanisms to animal physiology. They will also help understand the complex interactions between environment and genetics leading to atherosclerosis. Accomplishment of the above aims will unravel a central signaling component that may act as a sensor to respond to dietary cholesterol; modulation of its activity may be the preferable mode for the treatment of lipid disorders in the 21st century.

描述（由申请人提供）：冠状动脉疾病（CAD）仍然是我们社会中死亡和残疾的主要原因。在促进CAD的所有已知危险因素中，低密度脂蛋白（LDL） - 胆固醇的高血清水平是最重要的危险因素之一。该脂蛋白的血浆水平受遗传因素以及饮食脂肪和胆固醇的量的强烈影响。饮食修饰仍然是预防CAD的基石。我们对控制胆固醇稳态响应饮食胆固醇的调节机制的了解，以及通过胆固醇水平改变引发的信号通路的作用也有限。同样，这些信号通路与固醇反应元素结合蛋白（SREBPS）以及连接SREBP加工和胆固醇水平的机制之间的相互关系尚不清楚。我们工作的新兴图片是，肝LDL受体的调节是胆固醇稳态至关重要的，这是由于一些相互联系的调节信号通路的活性所致。我们先前已经表明，对于首次，蛋白激酶C（PKC）的特定同工型参与了培养的肝细胞中LDL受体表达的调节，这可能是通过胆固醇直接调节活性的。根据我们的最新结果，我们提出了PKC（PKCB）B异型的核心作用在调节胆固醇稳态中，通过调节所选基因对此过程至关重要的表达。在特定的目标1中，将通过评估该LDNase对整体胆固醇稳态的敲除的影响来确定PKCB在胆固醇稳态中的作用。对PKC的初步研究（缺乏小鼠强烈支持该激酶在控制血浆胆固醇对饮食中胆固醇含量变化的反应性方面的核心作用。胆固醇代谢。胆固醇代谢将在正常和PKCB突变体之间进行详细比较，将在特定的饮食中进行特定的饮食。特定目的的表达将与chpatic by in Hepatic Geners的表达相比。 PKCB会影响SREBP-2的表达及其蛋白水解处理，可能通过调节1次磷酸化来检查，最终将检查胆固醇和PKCB之间的同工型特异性相互作用的性质。 PKCB对胆固醇的研究不仅会确定PKCB在饮食引起的高胆固醇血症中的作用，而且还将确定该激酶调节的基因，以将调节机制与动物生理相关。它们还将帮助了解导致动脉粥样硬化的环境与遗传学之间的复杂相互作用。实现上述目的将揭示一个中心信号成分，可以充当对饮食胆固醇反应的传感器。对其活性的调节可能是21世纪脂质疾病治疗的首选模式。