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）：糖尿病患者的治疗能力缺陷并应对缺血性压力。造成这种损害的血管再生能力的机制知之甚少。最近，已确认内皮前体细胞（EPC）被募集到新血管形成部位。与正常对照小鼠相比，我们实验室中的初步工作表明，与正常对照小鼠相比，糖尿病小鼠（DB/DB，NOD和链蛋白酶诱导的）特异性缺陷，可以动员和募集内皮前体细胞（EPC）到伤口或缺血性肢体。 EPC在正常小鼠中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新生血管形成可以通过腺病毒介导的血管生成因子的过表达来纠正血管生成因子，例如血管生成素-1（ANG-1），这些因素（ANG-1）募集可以纠正糖尿病伤口愈合障碍和对缺血性不良反应的EPCS。我们研究的总体目的是了解EPC被动员和招募到伤口愈合中的组织的机制和对缺血的反应，并了解这些机制如何受到糖尿病的损害。我们的工作假设是募集骨髓来源的EPC对于触发伤口或缺血组织的快速新血管形成反应至关重要，并且该部位特异性的EPC募集在糖尿病中特别缺陷。为了检验这一假设，我们计划实验以实现以下特定目的： 1。证明动员和募集生长因子 2。确定血管生长因子动员和募集骨髓衍生的EPC到伤口或缺血组织的靶向区域的机制 3。确定EPC通过与居民细胞环境相互作用来协调局部血管生成反应的机制。