Cav-3 in Diabetic Myocardial Injury Following Ischemia/Reperfusion

 描述(申请人提供)：随着2型糖尿病患病率的持续上升，迫切需要有效预防糖尿病心血管并发症的干预措施，糖尿病心血管并发症占该人群死亡人数的50%。糖尿病阻断了心脏对多种促生存信号通路的反应，使心肌细胞更容易受到MI/R损伤的影响。导致糖尿病心脏中心脏保护信号“普遍”受损的分子机制尚不清楚。以Cav为中心的信号复合体在促进快速、精确和协调的信号转导方面发挥着重要作用，广泛参与细胞保护和生存。然而，Cav信号复合体是否以及如何改变并有助于心脏保护信号的损害仍不清楚。我们的初步实验表明，Cav3的硝化修饰和由此产生的Cav3与其伙伴蛋白的解离发生在2型糖尿病的早期发展阶段，阻断了Cav3依赖的信号转导。目前的应用将检验一种假设，即在糖尿病心脏中，由于特定Tyr残基上的Cav3硝化修饰(S)，多种心脏保护干预所需的心脏保护Cav3信号体受损，导致有利于生存的心脏保护信号级联的普遍丧失，从而导致糖尿病患者心肌梗死后死亡率增加。我们将利用先进的分子/细胞技术，结合体外和体内方法来鉴定特定的酪氨酸残基(S)，其硝化/氧化修饰导致心脏保护Cav3信号体的分解(特定目标1)，阻断其生物学功能(特定目标2)，并揭示恢复糖尿病心脏的心脏保护信号的新治疗策略(特定目标3)，最终目标是降低糖尿病患者的心血管死亡率。由本申请提议的研究产生的新数据将定义 新的导致糖尿病心脏心脏保护反应丧失的分子机制，并有可能识别新的心脏保护靶点，可能在早期发育的糖尿病阶段保存/恢复各种心脏保护信号。

 DESCRIPTION (provided by applicant): As the prevalence of type 2 diabetes continues to escalate, there is an urgent need for interventions that effectively prevent diabetic cardiovascular complications, which account for >50% of deaths in this population. Diabetes blocks the cardiac response to multiple pro-survival signaling pathways, rendering cardiomyocytes more susceptible to MI/R injury. The molecular mechanisms leading to "universal" impairment of cardio-protective signaling in the diabetic heart remain unclear. Cav-centered signaling complexes play essential roles in facilitating rapid, precise, and coordinated signal transduction broadly involved in cell protection and survival. However, whether and how Cav-signal complexes are altered and contribute to impairment of cardio-protective signaling remains unknown. Our preliminary experiments demonstrate that nitrative modification of Cav3 and resultant dissociation of Cav3 from its partner proteins occur during the early development phase of type 2 diabetes, blocking Cav3- dependent signaling. The current application will test a hypothesis that, in the diabetic heart, cardio-protective Cav3-signalsomes required by multiple cardio-protective interventions are impaired due to Cav3 nitrative modification at specific Tyr residue(s), resulting in the universal loss of pro-survival cardio-protective signaling cascades, contributing to increased diabetic patient mortality after MI. We will utilize advanced molecular/cellular technologies, and combine in vitro and in vivo approaches to identify the specific tyrosine residue(s) whose nitrative/oxidative modification results in disassembly of cardio-protective Cav3-signalsomes (Specific Aim 1), blocking their biological functions (Specific Aim 2), and reveal novel therapeutic strategies restoring cardio-protective signaling in the diabetic heart (Specific Aim 3), with the ultimate goal of reducing cardiovascular mortality in diabetic individuals. The novel data resulting from this application's proposed studies will define novel molecular mechanisms leading to the loss of cardio-protective response in diabetic heart, and potentially identify novel cardio-protective targets that may preserve/restore various cardio-protective signaling during early developmental diabetic stages.