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: 7475944
• 负责人: TIMOTHY M CROMBLEHOLME
• 金额: $ 29.55万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475944
• 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健康问题，影响着1600万美国人，每年新增80万病例。I型糖尿病患者在愈合伤口和对缺血应激做出反应的血管生成能力方面存在缺陷。导致血管再生能力受损的机制还知之甚少。最近，内皮前体细胞(EPC)被认为被招募到新生血管的部位。这项建议的主要研究人员，医学博士Timothy M Crombleholme(对血管生成和血管生成感兴趣的外科医生)和医学博士Robert M Cohen(对糖基化在糖尿病并发症中的作用感兴趣的糖尿病专家)组成了一个合作伙伴，研究I型糖尿病小鼠模型中内皮祖细胞功能受损的问题。初步工作表明，与正常对照组小鼠相比，NOD糖尿病小鼠在动员和招募内皮前体细胞(EPC)到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内皮祖细胞的一个重要作用，即阻断正常小鼠的EPC募集既损害了伤口愈合，也损害了对急性缺血的反应。糖尿病小鼠的这种功能障碍的再生新生血管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，血管生成因子招募内皮祖细胞。我们的总体目标是了解在伤口愈合和对缺血的反应中内皮祖细胞被动员和招募到靶组织的机制，并了解I型糖尿病是如何损害这些机制的。我们的工作假设是，骨髓来源的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是必不可少的，而特定部位的EPC募集在糖尿病中尤其不足。为了验证这一假设，我们计划实现以下具体目标： 1.证实I型糖尿病患者骨髓来源内皮祖细胞的动员和募集受到影响。 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内皮祖细胞到伤口或缺血组织靶区的机制。 3.探讨I型糖尿病改变EPC基因表达和功能的机制。