CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: PROJECT 1

糖尿病和肥胖研究卓越中心：项目 1

• 批准号: 8360414
• 负责人: Timothy E O'Toole
• 金额: $ 18.64万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360414
• 关键词: 1,2-diacylglycerol; Adhesions; Affect; Aldehyde Reductase; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cultured Cells; Defect; Diabetes Mellitus; Diabetic mouse; Diglycerides; Disease Progression; Endothelium; Funding; Grant; Hematopoietic; Integrins; Knockout Mice; Matrix Metalloproteinases; Mediating; Mesenchymal; Modeling; Mus; National Center for Research Resources; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Population; Principal Investigator; Property; Reactive Oxygen Species; Research; Research Infrastructure; Research Project Grants; Resources; Role; Source; Specificity; Spleen; Stem cells; Testing; Treatment Efficacy; United States National Institutes of Health; Variant; Vascularization; Wound Healing; base; cost; diabetic; impaired capacity; peripheral blood; polyol; repaired

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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 项目1：糖尿病中的内皮祖细胞（EPC）动员缺陷 糖尿病与广泛的心血管疾病有关，这些疾病的最佳特征是内皮功能障碍，其修复能力受损。该项目的中心假设是，这些血管异常是由于循环EPCs从骨髓中动员的缺陷而导致的循环EPCs的损失。为了验证这个假设，我们将： 1.定义糖尿病诱导的EPC群体的变化：使用I型和/或II型糖尿病的小鼠模型，我们将量化外周血、脾脏和骨髓中抗原性定义的EPC群体的水平;确定这些效应是否特异于早期/晚期或非单核细胞/单核细胞EPC;并确定这些效应在疾病进展期间何时变得突出。为了建立特异性，我们将确定糖尿病的影响是否是EPCs独有的，或者间充质（MSC）和造血（HSC）干细胞是否也受到影响; 2.阐明糖尿病限制EPC动员的机制：为了评估整合素介导的粘附的参与，我们将检查表达α 4变体的小鼠中α 4 β 1和EPC水平的特性。为了确定MMPs是否缺乏，我们将检查它们在糖尿病小鼠骨髓和培养细胞培养基中的水平。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）敲除小鼠中的EPC、二酰基甘油（DAG）、活性氧（ROS）和PKC活性水平;以及 3.评估EPC动员策略的修复效果：基于目标2研究，我们将检查干预措施在促进新生血管形成和伤口愈合方面的效果。 糖尿病的修复