Role Angiogenesis/Endothelial Progenitor Cells Diabetic

描述（由申请人提供）：糖尿病在无冠状动脉疾病（CAD）的情况下导致心肌功能障碍。这种情况，糖尿病性心肌病（DCM），一直被认为是导致糖尿病患者充血性心力衰竭和死亡率较高的原因。更严重的是长期糖尿病患者心肌梗死（Ml）后HF的发生，因为糖尿病在Ml后诱导不良的心脏重构，导致更严重的HF。合并或不合并CAD的糖尿病心衰（统称为糖尿病性心衰）对公众健康构成重大威胁，因为糖尿病发病率上升，医疗管理延长了糖尿病患者的寿命。尽管糖尿病性心衰有这些独特的特点，而且由于糖尿病性心衰预后不良，可预见的公共卫生灾难，但目前还没有针对糖尿病性心脏病主要病理生理问题的特异性治疗方法。我们最近发现血管生成受损（由先前存在的成熟内皮细胞形成新的脉管系统）和循环内皮祖细胞（EPCs）可用性降低在DCM的发展中起主要作用。最近发现的来自成人骨髓的内皮祖细胞有助于血管的新生发育（血管生成），这提高了利用这些细胞通过血管生成和血管生成过程诱导新血管形成来修复缺血/梗死心肌的可能性。该项目的长期目标是明确血管系统及其相关生物学因素在糖尿病性心衰发展中的作用，并建立更有效的治疗策略来治疗糖尿病性心衰。因此，在本提案中，我们设计了一系列实验来研究血管生成和血管生成在糖尿病性心衰发展中的作用以及EPC移植对糖尿病性心衰的影响。在Specific Aim 1中，我们将研究心肌血管生成缺陷和EPCs在糖尿病性心衰发展中的作用。在Specific Aim 2中，我们将通过DCM和糖尿病Ml模型探讨EPC移植对糖尿病性心衰的治疗作用。在Specific Aim 3中，我们将研究介导EPC移植治疗效果的潜在机制。在本系列实验中，我们将使用链脲佐菌素诱导的糖尿病大鼠和小鼠模型，对心脏和EPCs进行全面的功能、分子和组织病理学检查。我们预计，本提案中概述的实验结果将为糖尿病性心衰的病理生理特征和创新干细胞/祖细胞治疗在修复或预防糖尿病相关心肌损伤方面的应用提供新的见解。这些研究的成功完成将提供新的治疗策略，以解决导致主要发病率和死亡率的临床疾病，迄今为止，现有的临床治疗方法尚未充分解决这种疾病。

DESCRIPTION (provided by applicant): Diabetes leads to myocardial dysfunction in the absence of coronary artery disease (CAD). This condition, diabetic cardiomyopathy (DCM), has been postulated to contribute to higher incidences of both congestive HF and mortality in diabetic patients. Even more serious is the occurrence, of HF following myocardial infarction (Ml) in long-standing diabetics, as diabetes induces adverse cardiac remodeling after Ml and leads to more severe HF. HF in diabetes with or without CAD (collectively referred to as diabetic HF) poses a major threat to public health as the incidence of diabetes rises, and as medical management prolongs the life span of diabetics. Despite these unique features of diabetic HF and the foreseen public health disaster due to the poor prognosis of diabetic HF, there have been no specific therapies targeting the principal pathophysiologic problems of diabetic heart diseases. We recently identified that impaired angiogenesis (formation of new vasculature from pre-existing mature endothelial cells) and decreased availability of circulating endothelial progenitor cells (EPCs) play a major role in the development of DCM. Recent identification of EPCs derived from adult bone marrow, which contribute to de novo development of vessels (vasculogenesis), has raised the possibility of utilizing these cells to repair ischemic/infarcted myocardium by inducing new vessel formation through the processes of vasculogenesis and angiogenesis. The long-term goal of this project is to define the role of the vasculature and its related biological factors in the development of diabetic HF and to establish more effective therapeutic strategies to treat diabetic HF. Accordingly, in this Proposal, we designed a series of experiments to investigate the role of angiogenesis and vasculogenesis in the development of diabetic HF and the impact of EPC transplantation on diabetic HF. In Specific Aim 1, we will investigate the role of defective myocardial angiogenesis and EPCs in the development of diabetic HF. In Specific Aim 2, we will explore the therapeutic impact of EPC transplantation on diabetic HF by using DCM and diabetic Ml models. In Specific Aim 3, we will investigate potential mechanisms which mediate the therapeutic effect of EPC transplantation. For this series of experiments, we will use streptozotocin-induced diabetic rat and mouse models and perform comprehensive functional, molecular and histopathologic examinations on the hearts and EPCs. We anticipate that the results of the experiments outlined in this proposal will yield new insight into the pathophysiologic features of diabetic HF and the application of innovative stem/progenitor cell therapy for repairing or preventing myocardial injury associated with diabetes. The successful completion of these studies should provide novel therapeutic strategies to address a clinical disorder that accounts for major morbidity and mortality and has to date been inadequately addressed by available clinical therapies.