MOLECULAR BASIS OF DIABETIC CARDIOMYOPATHY

描述 申请人摘要 糖尿病心肌病是一个临床和流行病学上的重大问题 重要性 导致提出这一建议的试点研究首次， 确定了心肌收缩力动态刚度的特定变化， 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性心肌病 多因素，对观察到的刚度变化有主要贡献 由结缔组织增生、蛋白质交联引起 肌原纤维晚期糖化终产物（AGEs）沉积和损伤 与活性氧（ROS）有关。 心肌蛋白， 在糖尿病患者中， 糖基化或ROS损伤的程度将与 心肌动力学（粘弹性）的各种成分的变化 在同一个组织中。 从以前的研究来看，这些蛋白质最有可能 受到影响的是间质胶原蛋白，收缩蛋白，包括肌动蛋白 肌球蛋白和肌原纤维结合肌酸激酶。 发现强 改变的结构和功能之间的相关性将被跟踪， 确定是否可以在体外诱导类似的功能变化， 非糖尿病心肌。 化学处理将用于诱导糖化 或ROS损伤相同的心肌蛋白参与改变 糖尿病患者中发现的结构-功能相关性。 的疗效 各种药理学试剂（目前具有治疗意义的潜在的 AGE交联破坏剂）在逆转特定的结构和功能 在糖尿病心肌和模拟糖尿病心肌中发现的缺陷， 糖基化/ROS对非糖尿病人心肌的损伤。 这项研究将 有助于理解和治疗人类心肌病变， 由糖尿病引起，特别注意舒张功能 功能障碍 (End摘要）

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)