Endothelial Progenitor Cell Biology in Type 1 Diabetes

1 型糖尿病的内皮祖细胞生物学

• 批准号: 7125615
• 负责人: TIMOTHY M CROMBLEHOLME
• 金额: $ 31.05万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125615
• 关键词: Adenoviridae; NOD mouse; angiogenesis; angiogenesis factor; angiopoietins; disease /disorder model; fibroblast growth factor; gene expression; genetically modified animals; growth factor; hematopoietic stem cells; immunomagnetic separation; insulin dependent diabetes mellitus; ischemia; laser Doppler flowmetry; pathologic process; platelet derived growth factor; protein structure function; transfection /expression vector; ultrasound blood flow measurement; vascular endothelial growth factors; vascular endothelium; wound healing

DESCRIPTION (provided by applicant): Diabetes is an enormous public health problem affecting 16 million Americans with 800,000 new cases each year. Type I diabetic patients have a defect in their angiogenic capacity to heal wounds and respond to ischemic stress. The mechanisms responsible for this compromised vascular regenerative capacity are poorly understood. Recently, endothelial precursor cells (EPCs) have been recognized to be recruited to sites of neovascularization. The principal investigators of this proposal, Timothy M Crombleholme, MD (a surgeon with a research interest in angiogenesis and vasculogenesis) and Robert M Cohen, MD (a Diabetologist with a research interest in the role of glycosylation in complications of diabetes) have formed a collaboration to study the impaired function of EPCs in murine models of type I diabetes. Preliminary work shows that NOD diabetic mice are specifically deficient, compared to normal control mice, in their ability to mobilize and recruit endothelial precursor cells (EPCs) to wounds or ischemic limbs. An essential role for EPCs is supported by our preliminary data showing that blockade of EPC recruitment in normal mice impairs both wound healing and the response to acute ischemia. This dysfunctional regenerative neovascularization in diabetic mice can be corrected by adenoviral-mediated overexpression of angiogenic growth factors which recruit EPCs. Our overall objective is to understand the mechanisms by which EPCs are mobilized and recruited to a target tissues in wound healing and in response to ischemia and understand how these mechanisms are impaired by type I diabetes. Our working hypothesis is that recruitment of bone marrow derived EPCs is essential for triggering a rapid neovascularization response in a wound or ischemic tissue and that site specific EPC recruitment is specifically deficient in diabetes. In order to test this hypothesis we plan the following specific aims: 1. To demonstrate that mobilization and recruitment of bone marrow derived EPCs is compromised in type I diabetes. 2. To determine the mechanisms by which type I diabetes impairs angiogenic growth factors ability to mobilize and recruit bone marrow-derived EPCs to target areas of a wound or ischemic tissue. 3. To determine the mechanisms by which type I diabetes alters EPC gene expression and function.

描述（由申请人提供）： 糖尿病是一个巨大的公共卫生问题，影响着 1600 万美国人，每年新增 80 万例糖尿病病例。 I型糖尿病患者在愈合伤口和应对缺血应激的血管生成能力方面存在缺陷。人们对血管再生能力受损的机制知之甚少。最近，人们已经认识到内皮前体细胞（EPC）会被募集到新血管形成的部位。该提案的主要研究人员 Timothy M Crombleholme, MD（一位外科医生，对血管生成和血管发生有研究兴趣）和 Robert M Cohen, MD（一位糖尿病学家，对糖基化在糖尿病并发症中的作用有研究兴趣）组成了一个研究团队合作研究 I 型糖尿病小鼠模型中 EPC 功能受损的情况。初步研究表明，与正常对照小鼠相比，NOD 糖尿病小鼠在动员和募集内皮前体细胞 (EPC) 至伤口或缺血肢体的能力方面存在明显缺陷。我们的初步数据支持了 EPC 的重要作用，该数据显示，正常小鼠中 EPC 募集的阻断会损害伤口愈合和对急性缺血的反应。糖尿病小鼠中这种功能失调的再生性新血管形成可以通过腺病毒介导的血管生成生长因子的过度表达来纠正，从而招募EPC。我们的总体目标是了解在伤口愈合和缺血反应中 EPC 被动员和募集到目标组织的机制，并了解 I 型糖尿病如何损害这些机制。我们的工作假设是，骨髓源性 EPC 的募集对于在伤口或缺血组织中触发快速新生血管反应至关重要，而位点特异性 EPC 募集在糖尿病中尤其缺乏。为了检验这一假设，我们计划实现以下具体目标： 1. 证明骨髓源性 EPC 的动员和募集在 I 型糖尿病中受到损害。 2. 确定 I 型糖尿病损害血管生成生长因子动员和募集骨髓源性 EPC 到达伤口或缺血组织目标区域的能力的机制。 3. 确定I型糖尿病改变EPC基因表达和功能的机制。