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，子宫内环境中的不良情况会增加血管疾病的后代风险。尽管最初的报告集中在受限制的婴儿中，但数据表明母体糖尿病（DM）倾向于血管疾病。这些数据在一起表明，胎儿脉管系统非常容易受到损伤。血管健康的关键组成部分是完整的内皮功能。内皮的稳态调节需要在血液中循环的内皮细胞和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）编排血管修复和血管形成。此外，在成年人中进行的许多研究表明，外周血液EPC数量减少与血管疾病风险增加之间的相关性。但是，尚无研究检查儿童是否存在类似的相关性。这些数据共同构成了我们整体假设的基础。我们假设母体2型DM（T2DM）宫内环境使胎儿受到明显的压力，导致EPC数量减少，EPC功能能力损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识别。已经报道了两个具有不同功能特性的EPC亚群。然而，尽管数据表明两种EPC类型在血管修复中都是可操作的，但很少有研究评估了小儿受试者这些EPC的功能。该应用中概述的研究将直接询问是否两种EPC亚群的功能障碍涉及T2DM妊娠后代的内皮功能障碍，并检查EPC功能的过早衰老能力的贡献。阐明导致T2DM母亲后代血管疾病风险增加的基本机制对于寻找潜在的预防策略至关重要。此外，小儿研究提供了鉴定血管疾病风险的生物标志物的潜力，从而可以实施早期干预措施以破坏这种病理。公共卫生相关性：在此应用中，我们将直接询问内皮祖细胞的功能障碍是否参与了2型糖尿病母亲的后代内皮功能障碍。阐明负责2型糖尿病母亲后代血管疾病风险增加的基本机制对于寻找潜在的预防策略至关重要。