High throughput screens for fatty acid uptake inhibitors

高通量筛选脂肪酸摄取抑制剂

• 批准号: 7889078
• 负责人: Paul N. Black
• 金额: $ 36.38万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7889078
• 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 Delivery Systems; 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; Screening procedure; 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; uptake

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. PUBLIC HEALTH RELEVANCE: This research project addresses the need for pharmaceuticals to combat obesity and chronically high blood triglycerides and free fatty acids that result in diseases such as metabolic syndrome, cardiovascular disease and type 2 diabetes. These studies are a continuation of a methods development project aimed at selecting small compounds useful to inhibit fatty acid uptake into cells so that these toxic compounds cannot cause cell dysfunction and disease. Very few such drugs are currently in clinical use.

描述（由申请人提供）：代谢综合征、胰岛素抵抗性糖尿病和心血管疾病是目前美国和其他发达国家健康管理负担的主要原因。这些疾病的病因仍知之甚少。越来越多的证据表明脂肪酸代谢途径失调是一个主要致病因素。目前，只有有限数量的药物可用于对抗这些疾病，并且显然需要更狭窄地针对所涉及的代谢途径的新药物。在目前的工作中，我们寻求继续我们的方法开发项目，旨在识别和表征阻止脂肪酸转运的化合物，作为限制饮食脂肪吸收到易受过量脂肪酸毒性作用的细胞和组织（包括胰腺）的方法，肝脏和肌肉。我们还预计我们发现的一些化合物可用于专门减少肠道吸收，作为防止吸收多余脂肪热量的首要步骤。长期目标是识别区分脂肪酸类别的化合物，以防止细胞摄取和积累饱和和反式不饱和脂肪酸，同时允许多不饱和脂肪酸的吸收。本提案源于我们开发和测试高通量筛选方法的工作，以识别依赖于人类脂肪酸转运蛋白（FATP）的脂肪酸摄取抑制剂。在之前的资助期间，我们以酿酒酵母中表达的人类 FATP 为目标，建立并测试以高通量形式筛选脂肪酸摄取抑制剂的方法。我们现在计划扩展这些研究，通过采用针对特定器官的各种模型系统来表征在初步筛选的 100,000 种化合物中鉴定出的化合物，以完善我们的筛选方法，以用作针对肝脏和肠道脂肪酸摄取的先导药物，并检验假设一些非典型抗精神病药物通过抑制特定细胞类型摄取脂肪酸而引起代谢性血脂异常。 公共健康相关性：该研究项目解决了对抗肥胖和长期高甘油三酯和游离脂肪酸的药物需求，这些因素会导致代谢综合征、心血管疾病和 2 型糖尿病等疾病。这些研究是方法开发项目的延续，旨在选择可用于抑制细胞摄取脂肪酸的小化合物，从而使这些有毒化合物不会导致细胞功能障碍和疾病。目前临床使用的此类药物很少。