MOLECULAR BASIS OF DIABETIC CARDIOMYOPATHY

描述 申请人摘要 糖尿病心肌病是一个严重的临床和流行病学问题。 重要性。导致这一提议的试点研究第一次 可识别的心肌收缩动态刚度的特异性改变 和左心室组织的舒张期非收缩成分 糖尿病患者。我们的主要假设是糖尿病心肌病是 多因素，对观察到的刚度变化有主要贡献 引起结缔组织增殖，引起蛋白质交联化 晚期糖化终末产物(AGEs)的肌原纤维沉积和损害 与活性氧簇(ROS)有关。心肌蛋白质是 糖尿病患者会发现ROS过度糖化或受损 心肌，糖基化或ROS损伤的程度将与 心肌动力学(粘弹性)各成分的变化 同一组织中的僵硬程度。从之前的研究来看，这些蛋白质很可能 受影响的是间质胶原，包括肌动蛋白在内的收缩蛋白 肌球蛋白和肌原纤维结合的肌酸激酶。STRONG的发现 改变的结构和功能之间的相关性将被跟进 确定在体外是否可以诱导出类似的功能变化 非糖尿病心肌。将使用化学处理来诱导糖基化。 或ROS对参与改变的相同心肌蛋白的损伤 在糖尿病患者中发现结构与功能的相关性。的功效。 各种药理药剂(目前作为潜在的治疗药物 老化的交链断路器)在颠倒特定的结构和功能 糖尿病心肌和糖尿病模型心肌中发现的缺陷 糖基化/ROS对非糖尿病人心肌的损伤。这项研究将 有助于了解和治疗人类心肌病理 由糖尿病引起，特别注意舒张压 功能障碍。(摘要结束)

DESCRIPTION Applicant's Abstract Diabetic cardiomyopathy is a problem of great clinical and epidemiologic importance. Pilot studies leading to this proposal have, for the first time, identified specific alterations of myocardial dynamic stiffness of contractile and diastolic noncontratile components of left ventricular tissue from diabetic patients. Our primary hypothesis is that diabetic cardiomyopathy is multifactorial, with major contributions to the observed stiffness changes arising from connective tissue proliferation, protein crosslinking caused by deposition of myofibrillar advanced glycated end products (AGEs), and damage associated with reactive oxygen species (ROS). Myocardial proteins that are excessively glycated or damaged by ROS will be identified in diabetic myocardium, and the extent of glycation or ROS damage will be correlated with changes in various components of the myocardial dynamic (visco-elastic) stiffness in the same tissue. From previous studies, the proteins most likely to be affected are interstitial collagen, contractile proteins including actin and myosin, and myofibrillar-bound creatine kinase. Discovery of strong correlations between altered structure and function will be followed up by determining whether similar changes in function can be induced in vitro in non-diabetic myocardium. Chemical treatments will be used to induce glycation or ROS damage to the same myocardial proteins involved in altered structure-function correlations discovered in the diabetics. The efficacy of various pharmacological agents (currently of therapeutic interest as potential AGE cross-link breakers) in reversing the specific structural and functional defects found in diabetic myocardium and mock-diabetic myocardium prepared by glycation/ROS damage to non-diabetic human myocardium. This research will contribute to understanding and treating human myocardial pathologies that arise from diabetes mellitus, with particular attention to diastolic dysfunctions. (End of Abstract)