Targeting RAGE-mDia1 in Diabetic Complications: Mechanisms and Therapeutics

描述(申请人提供)：1型和2型糖尿病及其并发症呈上升趋势。在已批准的基于并发症的治疗和糖尿病并发症中已建立的疾病特异性生物标记物方面都存在公认的不足，这严重阻碍了临床试验。这一应用侧重于晚期糖基化终末产物受体(RAGE)及其细胞质结构域结合伙伴-哺乳动物形式的透明蛋白1，mDia1的作用，它对于RAGE信号作为糖尿病并发症的基本治疗靶点是必不可少的。为了将我们的发现转化为糖尿病并发症治疗方法的开发，我们进行了文库筛选，并鉴定了两个先导系列的小分子，它们抑制了RAGE Tail-mDia1与NM亲和力的相互作用，并在体外和体内实验测试中证明了有效性。我们已经开发了新的RAGE和mDia1牙线小鼠，以探索它们在糖尿病并发症中的细胞特异性贡献。我们的方法将涉及测试以下特定目标：目标1将寻求通过最大化药物样属性来优化阻断RAGE/mDia1信号转导的两个先导化合物系列；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信号转导促进糖尿病心脏缺血再灌注(I/R)损伤的机制；以及目标4将剖析RAGE-mDia1信号转导通过炎症分解受损而导致糖尿病并发症的机制，作为开发靶参与生物标志物的跳板。我们组建了一支多学科团队，拥有RAGE/mDia1信号转导和糖尿病并发症；结构生物学和核磁共振波谱；药物和计算化学；以及生物信息学/生物统计学的专业知识，以解决糖尿病并发症的治疗和靶向参与生物标记物的问题。

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.