Targeting RAGE-mDia1 in Diabetic Complications: Mechanisms and Therapeutics

描述（由申请人提供）：1型和2型糖尿病及其并发症正在上升。在糖尿病并发症中，公认缺乏已批准的基于并发症的治疗和已建立的疾病特异性生物标志物，这严重阻碍了临床试验。本申请的重点是晚期糖基化终末产物受体（CADR）及其胞质结构域结合伴侣（哺乳动物形式的透明蛋白1，mDia 1）的作用，这对CADR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的治疗方法的开发，我们进行了文库筛选，并确定了两个先导系列的小分子，它们以nM亲和力抑制mDia 1的相互作用，并在体外和体内实验测定中证明了功效。我们已经开发了新的mDia 1和mDia 1 floxed小鼠，以探测它们对糖尿病并发症的细胞特异性贡献。我们的方法将包括测试以下具体目标：AIM 1将寻求通过最大化药物样特性来优化阻断RAGE-mDia 1信号传导的两个先导化合物系列; Aim 2将剖析RAGE-mDia 1信号转导有助于糖尿病肾病发病机制的机制;目的3探讨RAGE-mDia 1信号转导在糖尿病心肌缺血再灌注损伤中的作用机制; Aim 4将剖析RAGE-mDia 1信号转导通过炎症消退受损而导致糖尿病并发症的机制，以作为开发靶点参与生物标志物的跳板。我们组建了一个多学科团队，他们拥有以下领域的专业知识：mDia 1/mDia 1信号转导和糖尿病并发症;结构生物学和NMR光谱学;药物和计算化学;以及生物信息学/生物统计学，以解决糖尿病并发症的治疗和靶向参与生物标志物的问题。

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.