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: 7271910
• 负责人: TIMOTHY M CROMBLEHOLME
• 金额: $ 30.15万
• 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/7271910
• 关键词: Acute; Affect; American; Amputation; Angiopoietin-1; Area; Biological; Blood Vessels; Bone Marrow; Cellular biology; Clinical; Collaborations; Complications of Diabetes Mellitus; Data; Defect; Diabetes Mellitus; Diabetic mouse; Exercise; Foot Ulcer; Gene Expression; Growth Factor; Hypertension; Impairment; Insulin-Dependent Diabetes Mellitus; Investigation; Ischemia; Laboratories; Limb structure; Modeling; Mus; Myocardial; Myocardial Ischemia; Numbers; Patients; Peripheral; Personal Satisfaction; Physiological; Principal Investigator; Protein Overexpression; Public Health; Recruitment Activity; Research; Role; Site; Smoking; Stem cells; Streptozocin; Stress; Surgeon; Testing; Tissues; Transgenes; Work; Wound Healing; adenoviral-mediated; angiogenesis; cardiovascular risk factor; diabetic; diabetic wound healing; glycosylation; hypercholesterolemia; interest; neovascularization; precursor cell; repaired; research study; response; revascularization surgery; type I diabetic; vasculogenesis; wound

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，影响了1600万美国人，每年有80万例新病例。 I型糖尿病患者的血管生成能力缺陷可以治愈伤口并应对缺血性压力。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。 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.初步工作表明，与正常对照小鼠相比，点头糖尿病小鼠在动员和募集内皮前体细胞（EPC）的能力方面特别缺陷。我们的初步数据表明，EPCS的重要作用表明，正常小鼠中EPC募集的封锁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血管化可以通过腺病毒介导的募集EPC的血管生长因子的过表达来纠正。我们的总体目标是了解EPC在伤口愈合和对缺血的反应中动员并招募到目标组织的机制，并了解这些机制如何受到I型糖尿病的损害。我们的工作假设是募集骨髓衍生的EPC对于触发伤口或缺血组织的新血管形成反应至关重要，并且该部位特定的EPC募集在糖尿病中特别缺乏。为了检验这一假设，我们计划以下具体目的： 1。证明骨髓衍生的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长因子的机制，使血管生成因子动员和募集骨髓衍生的EPC靶向伤口或缺血性组织的区域。 3。确定I型糖尿病的机制改变EPC基因的表达和功能。