High throughput screens for fatty acid uptake inhibitors

高通量筛选脂肪酸摄取抑制剂

基本信息

批准号：
8462593
负责人：
Paul N. Black
金额：
$ 29.16万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462593
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Address Adipocytes Adverse effects Animal Model Antipsychotic Agents Apoptosis Automobile Driving Biological Assay Biological Models Blood Calories Cardiovascular Diseases Cell Death Cell Line Cells Chemicals Clinical Complex Developed Countries Development Diabetes Mellitus Diet Dietary Fats Disease Drug Targeting Drug usage Dyslipidemias Etiology Family Fatty Acids Fatty acid glycerol esters Functional disorder Funding Goals Grant Health Benefit Human Hypertriglyceridemia Insulin Resistance Intestinal Absorption Intestines Intracellular Membranes Laboratories Lead Life Lipolysis Liver Mediating Metabolic Metabolic Diseases Metabolic Pathway Metabolic syndrome Metabolism Methods Mitochondria Modeling Mus Muscle Muscle Fibers Names Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Organ Oxidative Stress Pancreas Pharmaceutical Preparations Pharmacologic Substance Poison Polyunsaturated Fatty Acids Research Design Research Project Grants Saccharomyces cerevisiae Skeletal Muscle Source System Testing Therapeutic Tissues Toxic effect Triglycerides Unsaturated Fatty Acids Weight Gain Work Yeasts absorption atypical antipsychotic base biological adaptation to stress cell type combat extracellular fatty acid oxidation fatty acid transport fatty acid-transport protein high throughput screening inhibitor/antagonist method development prevent protein function public health relevance screening uptake

项目摘要

DESCRIPTION (provided by applicant): Metabolic syndrome, insulin resistant diabetes, and cardiovascular disease are currently major contributors to the burden of heath management in the US and other developed countries. The etiology of these diseases is still poorly understood. A growing body of evidence suggests dysregulation of fatty acid metabolic pathways is a major causative factor. Currently, only a limited number of drugs are available to combat these diseases and it is clear new drugs, which more narrowly target the metabolic pathways involved, are required. In the present work, we seek to continue our methods development project aimed at identifying and characterizing chemical compounds that prevent fatty acid transport as a method to limit dietary fat absorption into cells and tissues that are susceptible to toxic effects of excessive fatty acids including pancreas, liver and muscle. We also expect some of the compounds we identify may be employed to specifically reduce intestinal absorption as a primary step in preventing absorption of excess fat calories. A long-term goal is to identify compounds that distinguish between classes of fatty acids to prevent cellular uptake and accumulation of saturated and trans- unsaturated fatty acids, while permitting the absorption of polyunsaturated fatty acids. The present proposal follows from our work to develop and test methods for high throughput screening to identify inhibitors of fatty acid uptake dependent upon the human fatty acid transport proteins (FATP). In the previous funding period we targeted human FATP expressed in the yeast Saccharomyces cerevisiae to establish and test methods to screen for fatty acid uptake inhibitors in a high throughput format. We now plan to extend these studies to refine our screening methods by employing various model systems that target specific organs to characterize compounds identified in a preliminary screen of 100,000 compounds for usefulness as lead drugs targeting fatty acid uptake in liver and intestine and to test the hypothesis some atypical antipsychotics cause metabolic dyslipidemia by inhibiting fatty acid uptake into specific cell types.

描述（由申请人提供）：代谢综合征，胰岛素抵抗糖尿病和心血管疾病目前是美国和其他发达国家荒地管理负担的主要贡献者。这些疾病的病因仍然知之甚少。越来越多的证据表明，脂肪酸代谢途径失调是主要原因。当前，只有有限数量的药物可以与这些疾病作斗争，这是需要新的药物，而新药更狭窄地针对所涉及的代谢途径。在目前的工作中，我们试图继续我们的方法开发项目，旨在识别和表征化学化合物，以防止脂肪酸转运，作为将饮食中脂肪吸收限制为细胞和组织的方法，这些细胞和组织易受过多脂肪酸的毒性作用，包括胰腺，肝脏和肌肉。我们还期望我们确定的某些化合物可以专门降低肠道吸收，以此作为防止吸收过量脂肪卡路里的主要步骤。一个长期的目标是鉴定区分脂肪酸类别的化合物，以防止细胞摄取和饱和和不饱和脂肪酸的积累，同时允许吸收多不饱和脂肪酸。本提案遵循我们的工作，开发和测试高吞吐量筛查的方法，以鉴定脂肪酸摄取的抑制剂取决于人脂肪酸转运蛋白（FATP）。在上一个资金期间，我们针对酿酒酵母中表达的人FATP来建立和测试方法，以筛选高通量格式的脂肪酸摄取抑制剂。现在，我们计划扩展这些研究，通过采用针对特定器官的各种模型系统来完善我们的筛查方法，以表征在100,000个化合物的初步筛选中鉴定出的化合物，因为靶向肝脏和肠中脂肪酸吸收脂肪酸的铅药物，并测试某些非典型抗精神病药酸性的脂肪酸性细胞的脂肪酸对脂肪酸性造成的脂肪酸性造成脂肪酸性的酸性，从而对脂肪酸化进行了特定的酸性酸性。