Role of Angiogenesis and Endothelial Progenitor Cells in Diabetic Heart Failure

血管生成和内皮祖细胞在糖尿病心力衰竭中的作用

• 批准号: 7591147
• 负责人: Young-Sup Yoon
• 金额: $ 37.63万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591147
• 关键词: Accounting; Acute; Address; Adult; Affect; Animal Model; Attention; Attenuated; Biological Factors; Blood Vessels; Bone Marrow; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Cause of Death; Cell Therapy; Cells; Cessation of life; Chronic; Clinical; Comorbidity; Congestive Heart Failure; Coronary Arteriosclerosis; Defect; Development; Diabetes Mellitus; Disasters; Disease; Down-Regulation; Endothelial Cells; Functional disorder; Genes; Goals; Heart; Heart Diseases; Heart failure; Human; Hypertrophy; Incidence; Infarction; Injury; Investigation; Laboratories; Longevity; Mediating; Medical; Medicine; Modality; Modeling; Molecular; Morbidity - disease rate; Myocardial; Myocardial Degeneration; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pathogenesis; Pathology; Patients; Play; Population; Procedures; Process; Public Health; Research Personnel; Role; Series; Staging; Stem cell transplant; Stem cells; Streptozocin; Survivors; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Transplantation; Vascular Endothelial Growth Factors; angiogenesis; cohort; design; diabetic; diabetic cardiomyopathy; diabetic patient; diabetic rat; gene therapy; improved; innovation; insight; mortality; mouse model; neovascularization; non-diabetic; novel therapeutics; outcome forecast; peripheral blood; postnatal; prevent; progenitor; repaired; research study; stem; stem cell therapy; type I and type II diabetes; vasculogenesis

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.

在没有冠状动脉疾病（CAD）的情况下，糖尿病会导致心肌功能障碍。这个条件， 糖尿病性心肌病 (DCM) 被认为会导致充血性心力衰竭的发生率升高 和糖尿病患者的死亡率。更严重的是心肌梗塞后发生心力衰竭 (Ml) 对于长期糖尿病患者，因为糖尿病会在 Ml 后诱发不良心脏重塑，并导致更多 严重心力衰竭。伴有或不伴有 CAD 的糖尿病患者的心力衰竭（统称为糖尿病性心力衰竭）对以下人群构成重大威胁 随着糖尿病发病率的上升以及医疗管理延长人们的寿命，公共卫生 糖尿病患者。尽管糖尿病性心力衰竭具有这些独特的特征，并且由于贫困而可预见的公共卫生灾难 糖尿病心力衰竭的预后，目前尚无针对主要病理生理学的特异性治疗方法 糖尿病心脏病的问题。我们最近发现血管生成受损（新血管的形成） 来自预先存在的成熟内皮细胞的脉管系统）和循环内皮细胞的可用性降低 祖细胞 (EPC) 在 DCM 的发展中发挥着重要作用。最近鉴定的 EPC 衍生 来自成人骨髓，有助于血管的从头发育（血管发生），提高了 利用这些细胞通过诱导新血管形成来修复缺血/梗塞心肌的可能性 通过血管发生和血管生成的过程。 该项目的长期目标是确定脉管系统及其相关生物因素在 糖尿病心力衰竭的发展并建立更有效的治疗策略来治疗糖尿病心力衰竭。 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 糖尿病心力衰竭发生过程中的血管生成以及 EPC 移植对糖尿病心力衰竭的影响。在 具体目标1，我们将研究有缺陷的心肌血管生成和EPCs在发育中的作用 糖尿病性心力衰竭。在具体目标 2 中，我们将探讨 EPC 移植对糖尿病心力衰竭的治疗作用 通过使用 DCM 和糖尿病 M1 模型。在具体目标 3 中，我们将研究潜在的机制 介导EPC移植的治疗效果。对于这一系列的实验，我们将使用 链脲佐菌素诱导的糖尿病大鼠和小鼠模型，并进行全面的功能、分子和 对心脏和 EPC 进行组织病理学检查。我们预计实验结果 该提案中概述的内容将为糖尿病性心力衰竭的病理生理学特征和 应用创新干/祖细胞疗法修复或预防相关心肌损伤 患有糖尿病。这些研究的成功完成将为以下疾病提供新的治疗策略： 解决造成重大发病率和死亡率且迄今为止尚未得到充分解决的临床疾病 通过现有的临床疗法来解决。