Targeting RAGE-mDia1 in Diabetic Complications: Mechanisms and Therapeutics

靶向 RAGE-mDia1 治疗糖尿病并发症：机制和治疗

基本信息

批准号：
8876674
负责人：
Ravichandran Ramasamy
金额：
$ 79.7万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8876674
关键词：
Affinity Animals Anterior Descending Coronary Artery Anti-Inflammatory Agents Anti-inflammatory Binding Bioinformatics Biological Assay Biological Availability Biological Markers Biometry Breeding Cardiac Myocytes Cells Chemical Structure Chemistry Chronic Disease Clinical Trials Collaborations Complications of Diabetes Mellitus Computer Simulation Cytoplasmic Tail Data Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Disease Exhibits Foundations Future Genes Goals Health Healthcare Systems Heart In Vitro Infarction Inflammation Inflammatory Injury Insulin-Dependent Diabetes Mellitus Kidney Kidney Diseases Lead Left Libraries Life Ligands Ligation Mediator of activation protein Medical Research Mus Myosin Heavy Chains NMR Spectroscopy NPHS2 protein Non-Insulin-Dependent Diabetes Mellitus Operations Research Pathogenesis Peripheral Blood Mononuclear Cell Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Productivity Property Protein Binding Reperfusion Injury Reperfusion Therapy Research Contracts Research Personnel Resolution Rodent Role Safety Sclerosis Series Signal Transduction Smooth Muscle Myocytes Solubility Structure Structure-Activity Relationship Tail Testing Therapeutic Tissues analog base computational chemistry cost cost effectiveness design diabetic experience human subject improved in vivo in vivo Model indexing inhibitor/antagonist lead series macrophage novel podocyte receptor for advanced glycation endproducts recombinase screening small molecule structural biology targeted treatment therapeutic target therapy development translational study virtual

项目摘要

DESCRIPTION (provided by applicant): Types 1 and 2 diabetes and their complications are on the rise. There is a recognized lack in both approved complications-based therapies and established disease-specific biomarkers in diabetes complications, which significantly hinders clinical trials. This application focuses on the role of the receptor for advanced glycation endproducts (RAGE) and its cytoplasmic domain binding partner, mammalian form of diaphanous1, mDia1, which is essential for RAGE signaling as a fundamental therapeutic target for diabetic complications. To transform our discoveries from the bench to the development of therapies for diabetes complications, we performed a library screen and identified two lead series of small molecules that inhibit RAGE tail-mDia1 interaction with nM affinity and demonstrate efficacy in in vitro and in vivo experimental assays. We have developed novel RAGE and mDia1 floxed mice to probe their cell-specific contributions to diabetes complications. Our approach will involve testing the following specific aims: AIM 1 will seek to optimize the two lead compound series which block RAGE/mDia1 signaling by maximizing drug-like properties; Aim 2 will dissect the mechanisms by which RAGE-mDia1 signal transduction contributes to the pathogenesis of diabetic nephropathy; Aim 3 will dissect the mechanisms by which RAGE-mDia1 signal transduction contributes to the pathogenesis of ischemia-reperfusion (I/R) injury in the diabetic heart; and Aim 4 will dissect the mechanisms by which RAGE-mDia1 signal transduction contributes to diabetic complications via impaired resolution of inflammation, to serve as a springboard for the development of target engagement biomarkers. We have assembled a multi-disciplinary team with expertise in RAGE/mDia1 signal transduction and diabetes complications; structural biology and NMR spectroscopy; medicinal and computational chemistry; and bioinformatics/biostatistics to tackle the problem of therapies and target engagement biomarkers for diabetic complications.

描述（由申请人提供）：1 型和 2 型糖尿病及其并发症呈上升趋势。公认缺乏已批准的基于并发症的疗法和已建立的糖尿病并发症的疾病特异性生物标志物，这极大地阻碍了临床试验。该应用重点关注晚期糖基化终末产物 (RAGE) 受体及其胞质结构域结合伴侣（哺乳动物形式的 diaphanous1、mDia1）的作用，这对于 RAGE 信号传导作为糖尿病并发症的基本治疗靶点至关重要。为了将我们的发现从实验室转化为糖尿病并发症疗法的开发，我们进行了文库筛选，并鉴定了两个先导系列小分子，它们能够以 nM 亲和力抑制 RAGE tail-mDia1 相互作用，并在体外和体内实验测定中证明了功效。我们开发了新型 RAGE 和 mDia1 floxed 小鼠，以探究它们对糖尿病并发症的细胞特异性贡献。我们的方法将涉及测试以下具体目标：AIM 1 将寻求优化两个先导化合物系列，通过最大化药物样特性来阻断 RAGE/mDia1 信号传导；目标2将剖析RAGE-mDia1信号转导促进糖尿病肾病发病的机制；目标 3 将剖析 RAGE-mDia1 信号转导在糖尿病心脏缺血再灌注 (I/R) 损伤发病机制中的作用机制；目标 4 将剖析 RAGE-mDia1 信号转导通过炎症消退受损导致糖尿病并发症的机制，作为开发靶标参与生物标志物的跳板。我们组建了一支多学科团队，在 RAGE/mDia1 信号转导和糖尿病并发症方面拥有专业知识；结构生物学和核磁共振波谱；药物和计算化学；和生物信息学/生物统计学，以解决糖尿病并发症的治疗和目标参与生物标志物的问题。