Cellular mechanisms that promotes or prevent lipotoxicity

促进或预防脂毒性的细胞机制

基本信息

批准号：
7456185
负责人：
JEAN E. SCHAFFER
金额：
$ 24.93万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7456185
关键词：
Adipocytes Adipose tissue Affect Animal Model Apoptosis Apoptotic Biochemical Genetics Cardiac Myocytes Cardiomyopathies Cell Culture System Cell Death Cell Fractionation Cell Line Cells Chinese Hamster Ovary Cell Complementary DNA Condition Culture Media Cultured Cells Defect Development Diabetes Mellitus Disruption Endoplasmic Reticulum Event Exposure to Fatty Acids Functional disorder Gene Activation Gene Expression Generations Genes Genetic Genetic Screening Genome Goals Heart Heart failure Homeostasis Immunoblotting In Vitro Insertional Mutagenesis Insulin Resistance Label Lipids Measures Mediating Membrane Lipids Metabolic Metabolic Diseases Metabolic stress Mitochondria Modeling Molecular Molecular Target Mus Muscle Cells Mutagenesis Myoblasts Nonesterified Fatty Acids Obesity Oxidative Stress Palmitates Pathogenesis Pathway interactions Play Polymerase Chain Reaction Reactive Oxygen Species Role Saturated Fatty Acids Screening procedure Signal Pathway Stress Structure Supplementation Testing Time Transgenic Model Translating cell type diabetic cardiomyopathy fatty acid metabolism high throughput analysis in vivo in vivo Model insight mouse model mutant nonalcoholic steatohepatitis prevent promoter research study response

项目摘要

Excess lipid accumulation in non-adipose tissues is associated with cellular dysfunction and cell death that may contribute to the pathogenesis of insulin resistance, non-alcoholic steatohepatitis, and cardiomyopathy in diabetes and obesity. Mechanisms involved in these pathophysiologic responses have been studied in cultured cells by supplementation of growth media with high concentrations of free fatty acids. The saturated fatty acid palmitate leads to apoptosis in cultured cells by a mechanism involving oxidative stress and initiation of ER stress. This proposal will test the hypothesis that fatty acid perturbation of normal endoplasmic reticulum function is an early event in this lipotoxic cell death. Moreover, cells with gene disruptions that prevent lipotoxic cell death may have defects in fatty acid import and channeling or in the response to lipid-induced perturbations of endoplasmic reticulum function or oxidative stress. Our first three aims will employ biochemical and genetic approaches to identify molecular targets and signaling pathways in the lipotoxic response, In our fourth aim, we will translate our findings to mouse models relevant to diabetic cardiovascular disease in which lipid accumulation in cardiomyocytes is associated with heart failure. The results of these studies will characterize fundamental aspects of cellular lipid homeostasis. Moreover, these studies will provide new insights into the lipotoxic response to excess lipid accumulation in non-adipose tissues in diabetes and obesity.

非脂肪组织中的脂质积累过多与细胞功能障碍和细胞死亡有关可能有助于胰岛素抵抗，非酒精性脂肪性肝炎和心肌病的发病机理在糖尿病和肥胖症中。这些病理生理反应涉及的机制已在通过补充具有高浓度游离脂肪酸的生长培养基来培养细胞。饱和脂肪酸棕榈酸酯通过涉及氧化应激和的机制导致培养细胞的凋亡启动ER应力。该提议将检验以下假设：正常的脂肪酸扰动内质网络功能是这种脂肪毒性细胞死亡的早期事件。此外，具有基因的细胞防止脂肪毒性细胞死亡的破坏可能在脂肪酸进口和沟通中存在缺陷或对脂质诱导的内质网或氧化应激的反应。我们的前三个目标将采用生化和遗传方法来鉴定分子靶标和信号通路在我们的第四个目标中，脂毒性反应将我们的发现转化为与糖尿病相关的鼠标模型心血管疾病中脂质细胞中脂质的积累与心力衰竭有关。这这些研究的结果将表征细胞脂质稳态的基本方面。而且，这些研究将提供对非脂肪中脂质过量积累的脂毒反应的新见解糖尿病和肥胖症中的组织。