Diabetic Dyfuntion of CPCs

项目4的总体目标是确定糖尿病如何影响心脏祖细胞（CPC）介导的 梗死后心肌修复以及CPC治疗如何优化糖尿病心脏。 尽管使用CPC的干细胞治疗为心力衰竭的治疗提供了新的希望，但 干细胞治疗糖尿病仍不确定。我们的初步观察表明糖尿病 损害CPC生长和分化，与非糖尿病心脏相比，糖尿病心脏不 受益于CPC疗法。我们认为糖尿病通过诱导胰岛素降低CPC的活性 阻力糖尿病中过量的营养素会增加活性氧（ROS）的产生 引发炎症并在CPC中建立胰岛素抵抗。这反过来又削弱了他们的能力， 促进心肌修复。为了检验这一假设，提出了三个具体目标。(1)审查 葡萄糖转运和葡萄糖和脂肪酸代谢的CPC，我们将测量的速率， 在基础胰岛素水平下，从小鼠心脏分离的lin-/kit+ CPC中的糖酵解和脂肪酸代谢 条件和在高葡萄糖和棕榈酸的存在下，并确定如何营养过剩 影响CPC能力的基本参数。为了确定糖尿病的影响，我们将 从db/db和高脂喂养小鼠中分离CPC并将它们的能力与来自非 糖尿病小鼠(2)为了阐明营养过剩影响CPC的机制，我们将研究 炎症和氧化应激在诱导胰岛素抵抗中的作用， 在营养过剩或糖尿病的情况下，线粒体电子传递链过度活跃 导致ROS产生增加，从而引发促炎反应， 阻力(3)为了确定糖尿病对CPC介导的心肌修复的影响，我们将 在非糖尿病心脏中移植糖尿病CPC和在糖尿病心脏中移植非糖尿病CPC， 心肌梗死和测量CPC介导的心肌功能变化和试验的变化 是否抗炎或抗氧化干预，解决胰岛素抵抗促进CPC 在糖尿病和非糖尿病心脏中介导的心肌修复。 相关性（参见说明）： 大多数心力衰竭患者患有糖尿病，但糖尿病对干细胞治疗的影响 是未知的。通过提供对糖尿病影响的潜在机制的新理解， 干细胞治疗心力衰竭以及如何优化干细胞治疗糖尿病心脏， 该项目可能导致糖尿病心力衰竭治疗新疗法的开发， 和非糖尿病患者。

The overall goal of Project 4 is to detemine how diabetes affects cardiac progenitor cell (CPC)-mediated myocardial repair after infarction and how CPC therapy could be optimized for the diabetic heart. Although stem cell therapy with CPCs offers new hope for the treatment of heart failure, the efficacy of stem cell therapy in diabetes remains uncertain. Our preliminary observations show that diabetes impairs CPC growth and differentiation, and in contrast to non-diabetic hearts, diabetic hearts do not benefit from CPC therapy. We propose that diabetes decreases CPC competence by inducing insulin resistance. Excessive nutrients in diabetes increase the production of reactive oxygen species (ROS) that triger inflammation and establish insulin resistance in CPCs. This in turn impairs their capacity to promote myocardial repair. To test this hypothesis, three specific aims are proposed. (1) To examine glucose transport and glucose and fattty acid metabolism in CPCs, we will measure the rates of glycolysis and fatty acid metabolism in lin-/kit+ CPCs isolated from the mouse heart, under basal condition and in the presence of high glucose and palmitic acid and determine how nutrient excess affects the fundamental parameters of CPC competence. To determine the effect of diabetes, we will isolate CPCs from db/db and high-fat fed mice and compare their competence with CPCs from non- diabetic mice. (2) To elucidate the mechanisms by which nutrient excess affects CPCs, we will examine the role of inflammation and oxidative stress in inducing insulin resistance and test the hypothesis that in conditions of nutrient excess or diabetes, hyperactivity of the mitochondrial electron transport chain leads to an increase in ROS production which triggers pro-inflammatory responses resulting in insulin resistance. (3) To determine the impact of diabetes on CPC-mediated myocardial repair, we will transplant diabetic CPCs in non-diabetic hearts and non-diabetic CPCs in diabetic hearts after myocardial infarction and measure changes in CPC-mediated changes in myocardial function and test whether anti-inflammatory or anti-oxidant interventions that resolve insulin resistance promote CPC mediated myocardial repair in the diabetic and non-diabetic hearts. RELEVANCE (See instructions): A majority of patients with heart failure have diabetes, yet the effects of diabetes on stem cell therapy are unknown. By providing new understanding of the underlying mechanisms by which diabetes affects stem cell therapy in heart failure and how stem cell therapy could be optimized for the diabetic heart, this project could lead to the development of new therapies for the treatment of heart failure in diabetic and non-diabetic patients..