Probing an Unexplored Intracellular Pathway in Diabetes Pathogenesis

探索糖尿病发病机制中未探索的细胞内途径

基本信息

批准号：
10346402
负责人：
GEORGE C PRENDERGAST
金额：
$ 59.94万
依托单位：
LANKENAU INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10346402
关键词：
Acute Address Advanced Glycosylation End Products Amino Sugars Antidiabetic Drugs Autoimmune Automobile Driving Biological Markers Blood Vessels Cardiovascular system Cell physiology Cells Chronic Clinical Management Complex Complications of Diabetes Mellitus Consumption Coupled DNA Data Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Diet Elements Enzyme Inhibitor Drugs Enzymes Epitopes Etiology Event Fatty Liver Food Fructosamine Healthcare Systems Heart Hyperglycemia Inflammatory Ingestion Kidney Kidney Diseases Kidney Failure Knowledge Lead Liver Maillard Reaction Measures Mediating Meglumine Metabolic syndrome Methodology Methods Modality Monitor Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phosphotransferases Preclinical Drug Development Prediabetes syndrome Process Prognostic Marker Property Proteins Published Comment Publishing Research Research Personnel Research Proposals Role Series Serum Stress Structural Protein Structure-Activity Relationship Therapeutic Intervention Time Tissues Toxic effect Translational Research Triglycerides Unhealthy Diet Vulnerable Populations Weaning Work acute toxicity antagonist catalyst clinically relevant cost crosslink diabetes pathogenesis drug development enzyme pathway extracellular glycation improved inhibitor innovation insight lead candidate macrophage medication safety mouse model new therapeutic target non-alcoholic fatty liver disease nutrition population health prevent programs receptor repaired therapeutic development tool western diet

项目摘要

ABSTRACT Diabetic nephropathy and other diabetes complications impose enormous burdens on patients and healthcare systems, making it imperative to define actionable etiologic factors and develop effective, low-cost therapeutic interventions. Nonenzymatic protein glycation and the formation of advanced glycation end products (AGEs) are strongly implicated in pathogenesis. The driver of AGE formation is 3-deoxyglucosone (3DG), a highly reactive dicarbonyl species that also causes acute cellular toxicities by damaging enzymes and DNA and inflaming the vasculature. Accordingly, the ability to accurately measure 3DG levels and understand its etiology are paramount to elucidating pathogenesis, limiting its pathogenic effects, and improving clinical management of diabetic complications. Endogenous 3DG was deemed to arise nonenzymatically from the slow disintegration of glycated proteins in the body or absorbed from ingested heat-processed foods. We developed new methods to study the enzymatic activity of fructosamine-3-kinase (FN3K), an enzyme thought to repair glycated proteins and prevent AGE, but an end-product of FN3K activity is 3DG. We discovered that 3DG levels in kidney are higher than previously anticipated. Our core hypothesis is that FN3K-mediated 3DG formation in cells is a key pathogenic driver in diabetic complications. Specific Aim 1: we will measure 3DG arising in tissues in relationship to pathogenesis in the KK.Cg-Ay/J murine model of type-2 diabetes. Specific Aim 2: the impact of a high glycation diet on 3DG levels will be measured in tissues sensitive to diabetic complications, including in the kidney, heart, and liver of the diabetic mice. Specific Aim 3: We will define the pharmacodynamic properties and modes of action for meglumine, an agent, already proven safe, that we discovered has unrecognized medicinal effects, having provided nephroprotection and prevented triglyceride accumulation in diabetic mice. Specific Aim 4: a series of FN3K antagonists that we discovered will be characterized to identify a preclinical drug development candidate. This proposal offers several major innovative elements of high significance and impact in diabetes translational research. Aim 1 will provide new data developed with methodology we refined to measure FN3K activity and 3DG formation more accurately, addressing key gaps in knowledge. Aim 2 will explore the linkage between intracellular 3DG elevation and the consumption of ‘Western’ diets rich in fructosamines—the substrate for FN3K. Drug safety is paramount for any new diabetes drug. The data from Aim 3 will accelerate the development of meglumine as an innovative treatment modality—a compound proven extremely safe for chronic administration—to ameliorate diabetic nephropathy, fatty liver, and potentially other diabetic complications. Aim 4 offers opportunity to deliver first-in-class enzyme inhibitors as potential drug lead candidates. In summary, this research program will illuminate an unexplored intracellular pathway in diabetes pathogenesis and deliver unprecedented tools for broader research into the role of 3DG in diabetic nephropathy and other diabetes complications.

抽象的糖尿病肾病和其他糖尿病并发症给患者和医疗保健带来巨大负担系统，因此必须确定可行的病因并开发有效、低成本的治疗方法非酶促蛋白质糖化和晚期糖化终产物（AGE）的形成。 AGE 形成的驱动因素是 3-脱氧葡萄糖酮 (3DG)，它是一种高活性物质。二羰基物质也会通过破坏酶和 DNA 并使细胞发炎而引起急性细胞毒性。因此，准确测量 3DG 水平并了解其病因的能力至关重要。阐明发病机制，限制其致病作用，改善糖尿病的临床管理内源性 3DG 被认为是由糖化缓慢分解引起的。我们开发了新方法来研究体内的蛋白质或从摄入的热处理食品中吸收的蛋白质。果糖胺-3-激酶 (FN3K) 的酶活性，这种酶被认为可以修复糖化蛋白并预防 AGE，但 FN3K 活性的最终产物是 3DG 我们发现肾脏中的 3DG 水平高于肾脏。我们之前预期的核心假设是 FN3K 介导的细胞中 3DG 的形成是关键的致病因素。具体目标 1：我们将测量组织中产生的 3DG 的相关性。 2 型糖尿病 KK.Cg-Ay/J 小鼠模型的发病机制具体目标 2：高糖化的影响。饮食中的 3DG 水平将在对糖尿病并发症敏感的组织中进行测量，包括肾脏、心脏、具体目标 3：我们将确定其药效学特性和模式。葡甲胺的作用，一种已被证明安全的药物，我们发现它具有未被认识到的药用效果，为糖尿病小鼠提供肾保护并防止甘油三酯积聚。具体目标 4：a。我们发现的一系列 FN3K 拮抗剂将被表征以确定临床前药物开发该提案提供了对糖尿病具有重要意义和影响的几个主要创新要素。目标 1 将提供使用我们改进的测量 FN3K 的方法开发的新数据。目标 2 将探索更准确的活动和 3DG 形成，解决知识中的关键差距。细胞内 3DG 升高与食用富含果糖胺（底物）的“西方”饮食之间的关系对于任何新的糖尿病药物而言，药物安全性至关重要。Aim 3 的数据将加速这一进程。开发葡甲胺作为一种创新的治疗方式——一种被证明对慢性病极其安全的化合物给药——改善糖尿病肾病、脂肪肝和潜在的其他糖尿病并发症。 4 提供了提供一流酶抑制剂作为潜在候选药物的机会。研究计划将阐明糖尿病发病机制中未经探索的细胞内途径，并提供为更广泛地研究 3DG 在糖尿病肾病和其他糖尿病中的作用而发现的工具并发症。