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：
10331230
负责人：
Zoltan P Arany
金额：
$ 66.13万
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/10331230
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

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

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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.

项目摘要 /摘要骨骼肌和其他组织中的胰岛素抵抗（IR）对于2型糖尿病的发展是必不可少的。肌肉细胞中未完全氧化的非固定脂肪酸（FA）的过量积累，即脂毒性，越来越感谢IR发展的基础。并联，分支链氨基酸（BCAA）最近在糖尿病领域移动了前沿和中心，因为无偏代谢组分析前瞻性流行病学研究表明，BCAA的血清升高将IR和糖尿病视为临床表现前约20年。现在，我们发现了一种新型分子途径这两个观察结果。 BCAA valine在骨骼肌中的主动分解代谢会导致旁分泌代谢物，3-羟基异丁酸酯（3-HIB）的分泌，该分泌促进FAS进入骨骼肌，并随后的脂肪毒性。该途径的识别为潜在胰岛素抵抗的潜在治疗提供了一个新的入口点，与大多数当前基于胰岛素或胰岛素泌尿生成剂疗法的正交。拟议的项目回应 PA-16-374（测定开发和筛查以发现治疗或成像剂的疾病 NIDDK的兴趣），并将确定针对这个新发现的铅的小分子路径。 AIM 1在计算机和高通量筛选中使用，以鉴定阻断3HIB产生的分子。确定的命中将通过二次反屏幕的强大工作流进行。在AIM 2中，分子在AIM 1中鉴定出的将测试完整细胞的功效和安全性。在AIM 3中，AIM 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。那么可行的候选人将是测试了其阻断3HIB处理的小鼠中脂质积累和胰岛素耐药性的能力以及临床高脂喂养胰岛素抵抗模型。拟议的工作代表了学术界与强大的私营部门团队之间的密切合作成功的悠久历史。我们提出了一种新颖和挑衅的假设，以及以前未开发的理解和靶向脂肪毒性的方法。成功将产生新颖的目标和潜在的潜在客户开发新疗法的化合物，以解决胰岛素抵抗的根源。