High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes

高通量筛选血管脂肪转运调节剂以治疗和预防糖尿病

基本信息

批准号：
10343859
负责人：
Zoltan P Arany
金额：
$ 65.58万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343859
关键词：
Academia Address Amino Acids Automobile Driving Biochemical Biological Assay Blood Vessels Branched-Chain Amino Acids Catabolism Cell Survival Cells Clinical Coenzyme A Collaborations Development Diabetes Mellitus Disease Dose Endothelial Cells Endothelium Enoyl-CoA Hydratase Enzymes Epidemiology Evaluation Eye Fatty Acids Fatty acid glycerol esters Goals Human In Vitro Insulin Insulin Resistance Lead Link Lipids Measures Metabolic Modeling Molecular Morbidity - disease rate Mus Muscle Muscle Cells Muscle Fibers National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Oxides Pathway interactions Plant Roots Private Sector Process Production Recording of previous events Respiration Safety Serum Skeletal Muscle Specificity Structure Testing Text Therapeutic Agents Tissues Validation Valine Work assay development base counterscreen efficacy testing epidemiology study experimental study fatty acid transport high throughput screening imaging agent in silico in vivo in vivo Model interest metabolomics mortality mouse model novel novel therapeutics paracrine pharmacokinetics and pharmacodynamics pre-clinical prevent prospective response screening skeletal small molecule success trafficking uptake virtual

项目摘要

PROJECT SUMMARY / ABSTRACT Insulin resistance (IR) in skeletal muscle and other tissues is obligatory for the development of type 2 diabetes. Excess accumulation of incompletely oxidized non-esterified fatty acids (FAs) in muscle cells, i.e., lipotoxicity, is increasingly appreciated to underlie the development of IR. In parallel, branched chain amino acids (BCAAs) have recently moved front and center in the field of diabetes, as unbiased metabolomic profiling in large prospective epidemiological studies has shown that serum elevations of BCAAs predict IR and diabetes as much as 20 years prior to clinical presentation. We have now uncovered a novel molecular pathway that links these two observations. Active catabolism of the BCAA valine in skeletal muscle causes the paracrine secretion of a metabolite, 3-hydroxyisobutyrate (3-HIB), which promotes entry of FAs into skeletal muscle, and subsequent lipotoxicity. The identification of this pathway provides a novel entry point for the potential treatment of insulin resistance, orthogonal to most current insulin-based or insulin secretogenic therapies. The proposed project responds to PA-16-374 (Assay Development and Screening to Discover Therapeutic or Imaging Agents for Diseases of Interest to the NIDDK) and will identify lead-enabling small molecules that target this newly discovered pathway. Aim 1 use in silico and high-throughput screening to identify molecules that block production of 3HIB. Identified hits will be taken through a robust workflow of secondary counterscreens. In Aim 2, the molecules identified in Aim 1 will be tested for efficacy and safety in intact cells. In Aim 3, validated hits from Aims 1 and 2 will first be submitted to in vivo pharmacokinetic and pharmacodynamic studies. Viable candidates will then be tested for their ability to block lipid accumulation and insulin resistance in 3HIB-treated mice as well as in a pre- clinical high-fat fed model of insulin resistance. The proposed work represents a close collaboration between academia and a strong private sector team with a long history of successes. We propose a novel and provocative hypothesis, and a previously unexplored approach to understand and target lipotoxicity. Success would yield novel targets and potential lead compounds for the development of new therapeutics that address the root of insulin resistance.

项目概要/摘要骨骼肌和其他组织中的胰岛素抵抗（IR）是 2 型糖尿病发生的必然因素。肌肉细胞中不完全氧化的非酯化脂肪酸（FA）的过量积累，即脂毒性，越来越多的人认识到它是IR发展的基础。同时，支链氨基酸 (BCAA) 最近在糖尿病领域占据了前沿和中心，因为大范围的无偏见代谢组学分析前瞻性流行病学研究表明，血清 BCAA 升高可以预测 IR 和糖尿病临床表现前长达 20 年。我们现在发现了一种新的分子途径，将这两个观察结果。骨骼肌中支链氨基酸缬氨酸的活跃分解代谢导致旁分泌分泌代谢物 3-羟基异丁酸 (3-HIB)，促进 FA 进入骨骼肌，以及随后的脂毒性。该途径的鉴定为胰岛素抵抗的潜在治疗提供了一个新的切入点，与大多数当前基于胰岛素或胰岛素促分泌疗法正交。拟议项目响应 PA-16-374（检测方法开发和筛选，以发现治疗或显像剂的疾病 NIDDK 感兴趣），并将识别针对这一新发现的先导小分子途径。目标 1 使用计算机和高通量筛选来识别阻断 3HIB 产生的分子。已确定的命中将通过辅助柜台的强大工作流程进行。在目标 2 中，分子目标 1 中确定的药物将在完整细胞中进行功效和安全性测试。在目标 3 中，目标 1 和 2 的验证命中将首先提交体内药代动力学和药效学研究。可行的候选人将是在 3HIB 治疗的小鼠以及预治疗小鼠中测试了它们阻止脂质积累和胰岛素抵抗的能力。临床高脂喂养胰岛素抵抗模型。拟议的工作代表了学术界和强大的私营部门团队之间的密切合作悠久的成功历史。我们提出了一个新颖且具有争议性的假设，以及一个以前未探索过的假设理解和针对脂毒性的方法。成功将产生新的目标和潜在的领先优势用于开发解决胰岛素抵抗根源的新疗法的化合物。