Role Angiogenesis/Endothelial Progenitor Cells Diabetic

描述（由申请人提供）：糖尿病在没有冠状动脉疾病（CAD）的情况下导致心肌功能障碍。糖尿病性心肌病（DCM）被认为是糖尿病患者充血性心力衰竭和死亡率较高的原因。甚至更严重的是在长期糖尿病患者中心肌梗塞（MI）后HF的发生，因为糖尿病在MI后诱导不利的心脏重构并导致更严重的HF。随着糖尿病发病率的上升以及医疗管理延长了糖尿病患者的寿命，糖尿病伴或不伴CAD的HF（统称为糖尿病HF）对公众健康构成了重大威胁。尽管糖尿病HF具有这些独特的特征，并且由于糖尿病HF的不良预后而可预见的公共卫生灾难，但目前还没有针对糖尿病心脏病的主要病理生理问题的特异性疗法。我们最近发现，血管生成受损（从预先存在的成熟内皮细胞形成新的血管）和循环内皮祖细胞（EPCs）的可用性降低在DCM的发展中起着重要作用。最近鉴定的内皮祖细胞来源于成人骨髓，这有助于从头发展的血管（血管发生），提高了利用这些细胞修复缺血/梗死心肌的可能性，通过诱导新的血管形成，通过血管发生和血管生成的过程。本项目的长期目标是确定血管及其相关生物学因素在糖尿病HF发展中的作用，并建立更有效的治疗策略来治疗糖尿病HF。因此，在本研究中，我们设计了一系列实验来研究血管生成和血管发生在糖尿病HF发展中的作用以及EPC移植对糖尿病HF的影响。在具体目标1中，我们将研究缺陷心肌血管生成和EPCs在糖尿病HF发展中的作用。在具体目标2中，我们将通过使用DCM和糖尿病Ml模型来探索EPC移植对糖尿病HF的治疗影响。在具体目标3中，我们将研究介导EPC移植治疗效果的潜在机制。在这一系列实验中，我们将使用链脲佐菌素诱导的糖尿病大鼠和小鼠模型，并对心脏和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对糖尿病HF的病理生理特征和创新干/祖细胞治疗在修复或预防糖尿病相关心肌损伤中的应用产生新的见解。这些研究的成功完成应提供新的治疗策略，以解决导致主要发病率和死亡率的临床疾病，迄今为止，可用的临床治疗方法尚未充分解决。

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.