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，每年有80万新病例。I型糖尿病患者在其愈合伤口和对缺血性应激反应的血管生成能力方面存在缺陷。对这种受损的血管再生能力的机制知之甚少。最近，内皮前体细胞（EPCs）已被公认为被招募到新血管形成的网站。该提案的主要研究者，Timothy M Crombleholme，MD（对血管生成和血管发生感兴趣的外科医生）和Robert M Cohen，MD（对糖基化在糖尿病并发症中的作用感兴趣的糖尿病学家）已经形成了一个合作，以研究I型糖尿病小鼠模型中EPCs功能受损。初步研究表明，NOD糖尿病小鼠是特别缺乏，与正常对照小鼠相比，在他们的能力动员和招募内皮前体细胞（EPCs）的伤口或缺血肢体。我们的初步数据表明，正常小鼠中EPC募集的阻断损害伤口愈合和对急性缺血的反应，这支持了EPC的重要作用。糖尿病小鼠中这种功能失调的再生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，这些生长因子招募EPCs。我们的总体目标是了解EPCs在伤口愈合和缺血反应中动员和招募到靶组织的机制，并了解I型糖尿病如何损害这些机制。我们的工作假设是，骨髓来源的EPCs的募集对于在伤口或缺血组织中触发快速的新血管形成反应是必不可少的，并且位点特异性的EPC募集在糖尿病中是特别缺乏的。为了检验这一假设，我们计划实现以下具体目标： 1.证明骨髓来源的EPCs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来源的EPCs至伤口或缺血组织靶向区域的能力的机制。 3.确定I型糖尿病改变EPC基因表达和功能的机制。