Systemic vasculature remodeling in females: effects of the immune system and experience of pregnancy

女性全身脉管系统重塑：免疫系统和怀孕经历的影响

基本信息

批准号：
9900062
负责人：
ELIZABETH A. BONNEY
金额：
$ 39万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900062
关键词：
Acetylcholine Address Adipose tissue Adoptive Transfer Affect Animals Antigens Arterial Fatty Streak B-Lymphocytes Biology Blood Vessels CCR5 gene CD31 Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cell Communication Cell physiology Cells Cellular biology Collagen Data Disease Elements Experimental Models Fatty acid glycerol esters Female Functional disorder Future Generations Gestational Diabetes Granzyme Health Heart Diseases Homeostasis Hormonal Human Hypertension Immune Immune response Immune system Immunological Models Infiltration Inflammation Inflammatory Inflammatory Response Interleukin-15 Interleukin-17 Interleukin-7 Kidney Diseases Lead Leukocytes Life Link Longitudinal Studies Macrophage Activation Matrix Metalloproteinases Mediating Mesentery Mission Modeling Molecular Mothers Multiparity Mus National Heart, Lung, and Blood Institute National Institute of Child Health and Human Development Pathway interactions Phenotype Physiological Physiology Play Population Postpartum Period Pre-Eclampsia Predisposition Pregnancy Pregnancy Outcome Premature Birth Process Proteins Publishing Rag1 Mouse Regulation Regulatory T-Lymphocyte Research Resistance Resolution Risk Role Sex Differences Signal Transduction Stress Structure System T-Cell Depletion T-Lymphocyte TNF gene Testing Time Tissues United States Vascular System Vascular remodeling Vasodilator Agents Woman Women&apos s Health Work cardiovascular disorder risk cardiovascular health cardiovascular risk factor combat cytokine design disorder risk embryo/fetus antigen epidemiologic data experience human data immune activation macrophage men mouse model novel receptor recombinase reconstitution response sex stem tool trafficking vascular factor vascular injury vascular smooth muscle cell proliferation vascular stress

项目摘要

Heart disease is a significant killer of women in the United States. Heart disease is different in women as compared to men, and while hormonal milieu likely contributes to sex-specific cardiovascular physiology, the understanding of other mitigating factors is critical for the overall health. Epidemiologic data supports the idea that pregnancy is a driver of cardiovascular health risk. The physiologic stress of pregnancy reveals inherent cardiovascular strengths or deficiencies, enhances protective mechanisms, or has the potential to cause damage with cardiovascular consequences. Moreover, pregnancy-induced vascular adaptations continue postpartum (PP). The work proposed in this application stems from the basic idea that examination of cardiovascular biology soon after pregnancy is completed will give clues to the cardiovascular adaptations that persist long-term and therefore affect future cardiovascular disease risk. Study of these persistent adaptations is therefore expected to delineate mechanisms of sex-specific differences in cardiovascular biology. T cells play a role in hypertension and cardiovascular disease. Although pregnancy is a state of significant changes in the T cell pool, the PP status of these changes has not been completely elucidated, nor has it been examined in the context of maternal cardiovascular parameters. The PIs of this application are experts in the maternal immune system and in vascular biology and have partnered to provide preliminary evidence in a mouse model that immune deficiency in recombinase 1 deficient mice (Rag1-/-) modifies PP resistance vasculature physiology. The working model is that pregnancy generates T cells that are enhanced in their ability accumulate in perivascular tissues, that pregnancy increases the ability of vascular cells to interact with and respond to signals generated by T cells, and that this acquired state underlies the differences observed PP in vessels from normal and immune deficient animals. This R01 application proposes the following aims to test a specific model: Aim 1) Delineate the molecular mechanisms underlying PP perivascular tissue accumulation of T cells and macrophages and determine their role in PP vascular remodeling and function Aim 2) Determine the molecular basis relating CD8 T cell function to structural changes observed in PP systemic vasculature Aim 3) Define mechanisms underlying decreased PP vascular responses to Acetylcholine in CD8-reconstituted Rag1-/- as compared to un-manipulated Rag1-/- mice When examined in the context of existing human data, the information obtained will aid in designing relevant longitudinal studies in women, understanding the mechanisms linking T cell biology to PP vascular homeostasis, and in developing unique tools to delineate future cardiovascular disease risk in women. The proposed research addresses NHLBI strategic priorities, including Critical Challenges and Compelling questions related to sex differences in cardiovascular disease and also elements of the overall mission of NICHD.

心脏病是美国女性的重要杀手。女性心脏病不同与男性相比，荷尔蒙环境可能有助于特定性别的心血管生理学对其他缓解因素的理解对于整体健康至关重要。流行病学数据支持怀孕是心血管健康风险的驱动力的想法。怀孕的生理压力揭示了固有的心血管强度或缺陷，增强保护机制，或者有潜力造成心血管后果造成损害。此外，怀孕引起的血管适应继续产后（PP）。本申请中提出的工作源于以下基本思想怀孕后不久，心血管生物学将为心血管适应提供线索长期持续存在，因此影响未来的心血管疾病风险。这些持续改编的研究因此，预计将描述心血管生物学性别特异性差异的机制。 T细胞在高血压和心血管疾病中起作用。虽然怀孕是一种状态 T细胞池的显着变化，这些变化的PP状态尚未完全阐明，也没有是否在母体心血管参数的背景下进行了检查。该应用程序的PI是孕产妇免疫系统和血管生物学专家，并已合作提供初步在小鼠模型中的证据表明，重组酶1缺乏症的缺乏症（RAG1 - / - ）修饰PP 抗性血管生理。工作模型是妊娠产生了增强的T细胞在血管周围组织中积累的能力，怀孕增加了血管细胞的能力与T细胞产生的信号进行交互并响应，并且该获得的状态是差异的基础观察到来自正常和免疫缺陷动物的血管中的PP。此R01申请提出了以下目的是测试特定模型：目标1）描述PP细胞和巨噬细胞并确定其在PP血管重塑和功能中的作用目标2）确定CD8 T细胞功能与PP中观察到的结构变化的分子基础系统性脉管系统目的3）定义降低PP血管反应的机制在CD8重达中对乙酰胆碱的反应与未经操纵的rag1 - / - 小鼠相比，rag1 - / - 在现有人类数据的背景下进行检查时，获得的信息将有助于设计女性的相关纵向研究，了解将T细胞生物学与PP血管联系起来的机制体内平衡，并开发出独特的工具来描述女性未来心血管疾病的风险。这拟议的研究涉及NHLBI的战略重点，包括关键挑战和引人注目与心血管疾病的性别差异有关的问题以及整体任务的要素尼希德。