CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: PROJECT 1

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 项目1：糖尿病患者内皮祖细胞动员缺陷 糖尿病与一系列心血管疾病有关，这些疾病的最大特点是内皮功能失调，修复能力受损。该项目的中心假设是，这些血管异常是由于骨髓动员缺陷导致循环中的内皮祖细胞丢失所致。为了检验这一假设，我们将： 1.确定糖尿病引起的EPC群体的变化：利用I型和/或II型糖尿病的小鼠模型，我们将量化外周血、脾和骨髓中抗原性定义的EPC群体的水平；确定这些影响是否仅限于早期/晚期或非单核/单核细胞EPC；并确定这些影响在疾病进展期间何时变得突出。为了确定特异性，我们将确定糖尿病的影响是否仅限于内皮祖细胞，或者间充质干细胞(MSC)和造血干细胞(HSC)是否也受到影响； 2.描述糖尿病限制EPC动员的机制：为了评估整合素介导的黏附参与，我们将检测表达Alpha4变体的小鼠的Alpha4β1和EPC水平的特性。为了确定MMPs是否缺乏，我们将检测它们在糖尿病小鼠骨髓和培养细胞培养液中的水平。为了确定多元醇途径的作用，我们将表征糖尿病野生型和醛糖还原酶(AR)基因敲除小鼠的内皮祖细胞、二酰甘油(DAGs)、活性氧(ROS)和蛋白激酶C(PKC)活性水平；以及 3.评估EPC动员策略的修复效果：基于Aim 2研究，我们将检查干预措施在促进新生血管和伤口方面的效果 糖尿病的修复。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Project 1: Endothelial progenitor cell (EPC) mobilization defects in diabetes Diabetes is associated with a wide spectrum of cardiovascular diseases that are best characterized by a dysfunctional endothelium an impaired capacity for its repair. The central hypothesis of this project is that these vascular abnormalities result from a loss of circulating EPCs due to defects in their mobilization from the bone marrow. To test this hypothesis we will: 1. Define diabetes-induced changes in EPC populations: Using murine models of Type I and/or Type II diabetes, we will quantify levels of antigenically-defined EPC populations in peripheral blood, spleen and bone marrow; determine if these effects are specific to early/late or non-monocytic/monocytic EPCs; and determine when these effects become prominent during disease progression. To establish specificity, we will determine whether the effects of diabetes are unique to EPCs, or whether mesenchymal (MSC) and hematopoietic (HSC) stem cells are also affected; and 2. Delineate the mechanisms by which diabetes limits EPC mobilization: To assess the involvement of integrin-mediated adhesion, we will examine the properties of alpha4 beta1 and EPC levels in mice expressing alpha4 variants. To determine whether MMPs are deficient, we will examine their levels in the bone marrow of diabetic mice and in the media of cultured cells. To establish a role for the polyol pathway, we will characterize EPCs, diacylglycerols (DAGs), reactive oxygen species (ROS) and PKC activity levels in diabetic wild type and aldose reductase (AR) knockout mice; and 3. Evaluate the reparative efficacy of EPC mobilizing strategies: Based upon Aim 2 studies, we will examine the efficacy of interventions in promoting neo-vascularization and wound repair in diabetes.