Endothelial Progenitor Cell Recruitment in Diabetic Mice

糖尿病小鼠内皮祖细胞的募集

• 批准号: 7455220
• 负责人: TIMOTHY M CROMBLEHOLME
• 金额: $ 28.57万
• 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: 2005-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7455220
• 关键词: Acute; Affect; Amputation; Angiopoietin-1; Area; Biological; Blood Vessels; Bone Marrow; Clinical; Data; Defect; Diabetes Mellitus; Diabetic mouse; Eels; Exercise; Foot Ulcer; Growth Factor; Hypertension; Impairment; Investigation; Ischemia; Laboratories; Limb structure; Mus; Myocardial; Myocardial Ischemia; Numbers; Patients; Peripheral; Personal Satisfaction; Physiological; Protein Overexpression; Recruitment Activity; Research Personnel; Role; Site; Smoking; Stem cells; Streptozocin; Stress; Testing; Tissues; Transgenes; Work; Wound Healing; adenoviral-mediated; angiogenesis; cardiovascular risk factor; diabetic; diabetic wound healing; hypercholesterolemia; neovascularization; precursor cell; programs; repaired; research study; response; revascularization surgery; wound

DESCRIPTION (provided by applicant): Diabetic patients have a defect in their ability 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. Preliminary work in our laboratory shows that diabetic mice (db/db, NOD, and streptozotocin-induced) 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 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, such as Angiopoietin-1 (Ang-1) which recruit EPCs that can correct diabetic wound healing impairment and the poor response to ischemia. The overall objective of our investigations is to understand the mechanisms by which EPCs are mobilized and recruited to target tissues in wound healing and in response to ischemia and understand how these mechanisms are impaired by 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 experiments to achieve the following specific aims: 1. To demonstrate that mobilization and recruitment of growth factors 2. To determine the mechanism by which angiogenic growth factors mobilize and recruit bone marrow-derived EPCs to target areas of a wound or ischemic tissues 3. To determine the mechanisms by which EPCs orchestrate the local angiogenic response by interaction with resident cellular milieu.

描述（由申请人提供）：糖尿病患者愈合伤口和应对缺血应激的能力存在缺陷。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。我们实验室的初步工作表明，与正常对照小鼠相比，糖尿病小鼠（db/db、NOD 和链脲佐菌素诱导的）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。正常小鼠中 EPC 募集的重要作用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，例如血管生成素-1 (Ang-1)，它可以招募 EPC，从而纠正糖尿病伤口愈合障碍和对缺血的不良反应。我们研究的总体目标是了解在伤口愈合和缺血反应中EPCs被动员和募集到目标组织的机制，并了解糖尿病如何损害这些机制。我们的工作假设是，骨髓源性 EPC 的募集对于触发伤口或缺血组织中的快速新生血管反应至关重要，而糖尿病患者中，位点特异性 EPC 募集尤其缺乏。为了检验这一假设，我们计划进行实验以实现以下具体目标： 1. 证明生长因子的动员和招募 2. 确定血管生成生长因子动员和招募骨髓来源的 EPC 到伤口或缺血组织的目标区域的机制 3. 确定EPCs通过与常驻细胞环境相互作用协调局部血管生成反应的机制。