Endothelial Progenitor and Vascular Dysfunction in Infants of Diabetic Mothers

糖尿病母亲的婴儿的内皮祖细胞和血管功能障碍

基本信息

批准号：
8307245
负责人：
Laura S Haneline
金额：
$ 54.79万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307245
关键词：
Activities of Daily Living Adult Aftercare Animal Model Biochemical Biological Markers Blood Blood Vessels Blood flow Cardiovascular Diseases Cell Count Cell Wall Cell physiology Cells Characteristics Child Childhood Colony-forming units Complex Data Development Diabetic mother Early treatment Endothelial Cells Endothelium Environment Exhibits Exposure to Fetus Flow Cytometry Functional disorder Growth Health Hematopoietic stem cells Hydrogen Peroxide Hyperglycemia In Vitro Infant Inflammation Mediators Injection of therapeutic agent Injury MAP3K5 gene Methods Mothers Neonatal Non-Insulin-Dependent Diabetes Mellitus Outcome Oxidants Oxidation-Reduction Oxidative Stress Pathology Perinatal Exposure Pregnancy Premature aging syndrome Property Proteins Regulation Reporting Risk Stem cells Stress Testing Umbilical Cord Blood Vascular Diseases Woman base biological adaptation to stress cardiovascular disorder risk cell type diabetic disorder risk fetal in utero in vivo infant of diabetic mother macrophage maternal diabetes offspring oxidant stress peripheral blood progenitor repaired response senescence stressor vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): Significant evidence demonstrates that an adverse in utero environment increases offspring risk for vascular disease. While initial reports focused on growth restricted infants, data suggest that maternal diabetes (DM) predisposes offspring to vascular disease. Together these data suggest that the fetal vasculature is highly susceptible to injury. A critical component of vascular health is intact endothelial function. Homeostatic regulation of the endothelium requires dynamic interactions between endothelial cells and cells circulating in the blood to sustain endothelial function. Importantly, endothelial progenitor cells (EPCs) orchestrate vascular repair and vessel formation. Additionally, numerous studies in adults demonstrate a correlation between reduced peripheral blood EPC numbers and function with increased vascular disease risk. However, no studies have examined whether a similar correlation exists in children. Together these data form the basis for our overall hypothesis. We hypothesize that a maternal type 2 DM (T2DM) intrauterine environment subjects the fetus to significant stress resulting in decreased EPC numbers, loss of EPC functional capacity, and increased risk for endothelial dysfunction in offspring. EPC subpopulations can be identified by culture methods and flow cytometry. Two EPC subpopulations with distinct functional properties have been reported. However, few studies have evaluated the function of these EPCs from pediatric subjects, despite data indicating that both EPC types are operative in vascular repair. Studies outlined in this application will directly interrogate whether dysfunction of both EPC subpopulations are involved in endothelial dysfunction of offspring from T2DM pregnancies and examine the contribution of premature aging in the functional capacity of EPCs. Elucidating the underlying mechanisms responsible for the increased risk of vascular disease in offspring of T2DM mothers is paramount to finding potential preventative strategies. Further, pediatric studies offer the potential to identify biomarkers of vascular disease risk such that early interventions may be implemented to disrupt this pathology. PUBLIC HEALTH RELEVANCE: In this application, we will directly interrogate whether dysfunction of endothelial progenitor cells are involved in endothelial dysfunction of offspring from mothers with type 2 diabetes. Elucidating the underlying mechanisms responsible for the increased risk of vascular disease in offspring of type 2 diabetic mothers is paramount to finding potential preventative strategies.

描述（由申请人提供）：大量证据表明，子宫内的不良环境会增加后代患血管疾病的风险。虽然最初的报告主要关注生长受限的婴儿，但数据表明，母亲糖尿病 (DM) 会使后代容易患血管疾病。这些数据共同表明胎儿脉管系统非常容易受到损伤。血管健康的一个重要组成部分是完整的内皮功能。内皮的稳态调节需要内皮细胞和血液中循环的细胞之间的动态相互作用以维持内皮功能。重要的是，内皮祖细胞（EPC）协调血管修复和血管形成。此外，大量针对成人的研究表明，外周血 EPC 数量和功能减少与血管疾病风险增加之间存在相关性。然而，没有研究检验儿童是否存在类似的相关性。这些数据共同构成了我们总体假设的基础。我们假设母体 2 型糖尿病 (T2DM) 宫内环境使胎儿承受显着的压力，导致 EPC 数量减少、EPC 功能丧失以及后代内皮功能障碍的风险增加。 EPC亚群可以通过培养方法和流式细胞术来鉴定。已报道了两个具有不同功能特性的 EPC 亚群。然而，尽管有数据表明这两种 EPC 类型都可用于血管修复，但很少有研究评估儿科受试者的这些 EPC 的功能。本申请中概述的研究将直接询问两个 EPC 亚群的功能障碍是否与 T2DM 妊娠后代的内皮功能障碍有关，并检查过早衰老对 EPC 功能的影响。阐明 T2DM 母亲后代血管疾病风险增加的根本机制对于寻找潜在的预防策略至关重要。此外，儿科研究提供了识别血管疾病风险生物标志物的潜力，以便可以实施早期干预措施来破坏这种病理学。公共健康相关性：在本申请中，我们将直接询问内皮祖细胞功能障碍是否与 2 型糖尿病母亲的后代的内皮功能障碍有关。阐明 2 型糖尿病母亲的后代血管疾病风险增加的根本机制对于寻找潜在的预防策略至关重要。