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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

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