RYANODINE RECEPTOR DYSFUNCTION IN DIABETIC HEARTS

申请人摘要 肌浆网通过2型ryanodine释放钙离子 受体（RyR2）是导致以下事件级联的一个组成步骤： 心肌收缩研究表明，这一过程 在糖尿病大鼠的心脏中受损（Yu和麦克尼尔1991; Yu等人1994）。 我们最近发现，RyR2活性的降低源于一种 这种蛋白质的功能障碍，而不是减少其表达（Bidasee et al manuscript #1）。 迄今为止，RyR2功能障碍的分子基础 不知道。 我们的工作假设是"糖尿病改变了 RyR2上的钙外排途径。"在这个项目中，我们希望描述 糖尿病诱导的RyR2的变化，并确定这些变化的影响。 内源性调节剂对RyR2调节的变化。 与此同时， 我们想研究胰岛素和维拉帕米的有益作用 治疗包括逆转糖尿病诱导的RyR2蛋白的变化。 我们 具体目标是：（1）鉴定和表征RyR2的分子变化 糖尿病诱导的蛋白质，（2）以确定这些变化是否改变了 RyR2对内源性调节剂如Ca2+、pH等的敏感性，(3)到 确定长期糖尿病诱导的RyR2变化是否可以 用胰岛素治疗逆转，（4）确定维拉帕米治疗是否 可以保护和/或逆转糖尿病诱导的RyR2的变化，和（5） 确定维拉帕米和胰岛素联合治疗是否对 逆转糖尿病诱导的RyR2变化。 实现这些目标 这将有助于我们更好地理解 降低糖尿病中RyR2蛋白（以及可能的其他蛋白）的活性 这可能会导致对治疗策略的新见解， 减轻糖尿病引起的心脏功能障碍。

Applicant's Abstract Release of calcium ions from the sarcoplasmic reticulum via type 2 ryanodine receptors (RyR2) is an integral step in the cascade of events leading to cardiac muscle contraction. Studies have shown that this process is compromised in heart of diabetic rats (Yu and McNeill 1991; Yu et al. 1994). We recently found that the decrease in activity of RyR2 stems from a dysfunction of this protein rather than a decrease its expression (Bidasee et al manuscript #1). To date, the molecular basis for the dysfunction of RyR2 is not known. Our working hypothesis is "diabetes alters the integrity of the calcium efflux pathway on RyR2." In this project we want to characterize changes in RyR2 induced by diabetes and to determine the effects of these changes on the regulation of RyR2 by endogenous modulators. At the same time, we want to investigate whether the beneficial effects of insulin and verapamil treatments include reversal of diabetes-induced changes to RyR2 protein. Our specific aims are: (1) to identify and characterize molecular changes to RyR2 protein induced by diabetes, (2) to ascertain whether these changes alter the sensitivity of RyR2 to endogenous modulators like Ca2+, pH etc., (3) to determine whether changes to RyR2 induced by long-term diabetes can be reversed with insulin treatment, (4) to determine whether verapamil treatment can protect and/or reverse diabetes-induced changes to RyR2, and (5) to establish if verapamil and insulin co-treatments have additive effects on reversing changes to RyR2 induced by diabetes. Accomplishment of these aims will contribute significantly to understanding the molecular basis for the decrease activity of RyR2 protein (and possibly other proteins) in diabetes and this could lead to newer insights into therapeutic strategies for alleviating diabetes-induced dysfunction of the heart.