Genetic Editing of Ca Cycling in Diabetic Cardiomyopathy

糖尿病心肌病钙循环的基因编辑

• 批准号: 7261433
• 负责人: Roger J. Hajjar
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261433
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adult; Affect; Animal Model; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiac Myocytes; Consumption; Coupling; Defect; Diabetes Mellitus; Functional disorder; Gene Expression; Gene Transfer; Genetic; Goals; Heart; Heart failure; Human; Hypertrophy; In Vitro; Insulin; Intervention; Left; Link; Mechanics; Mediating; Metabolic; Metabolism; Molecular; Molecular Profiling; Muscle Cells; Myocardial; Numbers; Pathway interactions; Pattern; Performance; Phosphatidylinositols; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Protein Overexpression; Proteins; Rattus; Relaxation; Research; Research Personnel; Role; SERCA2a; SLC2A1 gene; Sarcoplasmic Reticulum; Signal Pathway; Signal Transduction Pathway; Signaling Molecule; Testing; Ventricular; Viral Vector; Work; diabetic; diabetic cardiomyopathy; diabetic rat; glucose metabolism; glucose uptake; heart preservation; improved; in vivo; insulin signaling; mutant; phospholamban; prevent; programs; restoration; type I and type II diabetes; uptake

DESCRIPTION (provided by applicant): Diabetes impairs left ventricular systolic and diastolic function and is associated with a number of abnormalities at the cellular level in the various steps of excitation-contraction coupling and signaling pathways. Two key abnormalities in experimental diabetic cardiomyopathy are a defect in sarcoplasmic reticulum (SR) function, which is associated with abnormal intracellular calcium handling, and a reduction in phosphatidyl-inositol 3-OH (PI3-) kinase activity and GLUT-4 expression. Deficient SR Ca2+ uptake during relaxation has been identified in diabetic hearts and has been associated with a decrease in the expression and activity of SR Ca2+-ATPase (SERCA2a). Furthermore, a decrease in PI3 kinase activity leading to a decrease in Akt activation and subsequently a decrease in GLUT-4 expression leads to impaired glucose uptake and hypertrophy. Using gene transfer to target specific pathways in cardio-myocytes, we will try to understand whether the excitation-contraction coupling changes in diabetic hearts occur before overt heart failure develops and/or participate in the initiation or the worsening of the changes. We will test the following hypotheses: 1) that the decrease in PI3-Kinase activity is linked to the EC coupling pathways and so contributes to the contractile dysfunction in diabetic hearts: 2) that metabolic interventions will protect against cardiac contractile dysfunction in diabetic hearts: and 3) that modulation of insulin-mediated signal transduction pathways in vivo can favorably modulate alterations of the EC coupling pathways and improve cardiac energetics and survival in diabetic rats. To test these hypotheses, we will use viral vectors to express wild-type and mutant forms of specific signaling molecules in cardiomyocytes in vitro and in vivo. We will examine the effects of PI3-Kinase, Akt, and GLUT-4 on contractile function, energetics and survival and remodeling in diabetic cardiomyopathic hearts. Animal models of type 1 and type 2 diabetes will be utilized in addition to primary cultures of human and adult rats ventricular myocytes.

描述（由申请人提供）：糖尿病会损害左心室收缩和舒张功能，并在激发触发偶联和信号通路的各个步骤中与细胞水平的许多异常有关。实验性糖尿病心肌病的两个关键异常是肌质网（SR）功能的缺陷，与异常的细胞内钙处理有关，磷脂酰肌醇3-OH（PI3-）激酶活性和Glut-4表达的降低。在糖尿病心脏中发现了在松弛过程中的SR Ca2+摄取不足，并且与SR Ca2+ -ATPase（SERCA2A）的表达和活性降低有关。此外，PI3激酶活性的降低导致AKT激活降低并随后降低GLUT-4表达会导致葡萄糖摄取和肥大受损。使用基因转移来靶向心肌细胞中的特定途径，我们将尝试了解糖尿病心脏的激发耦合变化是否发生在明显的心力衰竭发展和/或参与变化的启动或加剧之前。我们将测试以下假设：1）PI3-激酶活性的降低与EC耦合途径有关，因此有助于糖尿病心脏的收缩功能障碍：2）代谢干预将在糖尿病心脏中预防糖尿病的心脏疾病中的糖尿病性转变，并在糖尿病上的转变中脱离了胰岛素介导的途径：和3）胰岛素介导的媒介pation in viv in viv in viv in viv in viv in viv in viv in viv in viv ins in viv ins in viv ins in viv ins in viv ins to ins consection in and contrice hearts in and Insight consection。耦合途径并改善糖尿病大鼠的心脏能量和生存。为了检验这些假设，我们将使用病毒载体在体外和体内表达特定信号分子的野生型和突变形式的特定信号分子。我们将研究PI3-激酶，AKT和GLUT-4对糖尿病心肌病心脏中收缩功能，能量和生存以及重塑的影响。除人类和成年大鼠心室心肌细胞的原发性培养外，还将利用1型和2型糖尿病的动物模型。