Early Life Stress Induced Mechanisms of Cardiovascular Disease Risk and Resilience

生命早期压力诱发心血管疾病风险和恢复力的机制

• 批准号: 10555121
• 负责人: Jennifer S Pollock
• 金额: $ 224.27万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555121
• 关键词: Address; Adolescence; Adolescent; Adult; Animal Model; Basic Science; Bioinformatics; Biometry; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Central Nervous System; Child; Child Rearing; Clinic; Clinical; Collaborations; Data; Data Analytics; Diastolic blood pressure; Diet; Economics; Elderly; Endothelium; Ensure; Europe; Exposure to; Functional disorder; Future; Goals; Grant; Health; Healthcare; Heart Rate; Household; Human; Hypertension; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Life; Life Stress; Macrophage; Manuscripts; Measurement; Mediating; Mentors; Mission; Molecular; National Heart, Lung, and Blood Institute; North America; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Physical activity; Physiologic pulse; Prevention; Prevention strategy; Program Research Project Grants; Psychological Stress; Publications; Recording of previous events; Reproducibility; Risk; Risk Factors; Rodent; Rodent Model; Sampling; Sexual abuse; Specimen; Stressful Event; Structure; System; Techniques; Technology; Telemetry; Temperature; Translating; Translations; Vascular Diseases; Vascular Endothelium; Vascular resistance; Work; abuse neglect; blood pressure control; cardiovascular disorder risk; care burden; circadian; clinically relevant; cost; data management; disorder risk; early life stress; effective therapy; emerging adult; epigenome; experience; gut microbiome; immune activation; insight; lifestyle factors; metabolome; monocyte; multiple omics; neural network; novel; physical abuse; programs; prospective; protective factors; resilience; stressor; synergism; transcriptome; translational potential; translational study; traumatic event; violence exposure

OVERALL SUMMARY Early life stress (ELS) is defined as stressful and traumatic events, such as household dysfunction, neglect, sexual or physical abuse, economic hardship, and exposure to violence, experienced up to 18 years. ELS was identified as a cardiovascular disease (CVD) risk factor over 20 years ago, but mechanistic insights into its effects remain very limited. Exposure to ELS is pervasive in the US with ~50% of children and adolescents having one or more major ELS experiences. ELS exposure increases the risk traditional CVD risk factors - by the 3rd-4th decade of life. A recent analysis of healthcare burden in Europe and North America attributed $748 billion in annual costs to the effects of ELS, with 75% of those costs in people with multiple ELS exposures. The significance of our work aligns with the NHLBI mission to promote the prevention and treatment of cardiovascular diseases enhancing the health of all individuals to live longer and fulfilling lives. Among individuals with a history of ELS exposure, vascular dysfunction (elevated peripheral vascular resistance, increased vascular stiffness) and elevated diastolic blood pressure are already evident in early adulthood. The overall goal of our program project grant (PPG) is to define mechanisms by which ELS leads to CVD risk and inform strategies for prevention and effective treatment of CVD consequences in individuals exposed to ELS. This PPG will address two critical barriers to fulfill our goal: 1) Need for ELS-specific in-depth mechanistic and translational studies; and, 2) Identify modifiable protective factors that can reduce ELS-induced CVD risk. The overarching hypothesis of our PPG is that ELS induces immune cell activation leading to vascular dysfunction with increased hypertension risk and CVD risk that are exacerbated by later life stressors or moderated by resilience/protective factors. This PPG with both basic science and clinical projects utilizes a synergistic and integrative approach translating concepts from clinically relevant rodent models to humans. Our group is extremely synergistic, with each leader bringing unique expertise from different scientific backgrounds focused on our overall goal to understand mechanisms of ELS induced indicators of CVD risk and resilience. Over the past several years, our team built strong collaborations translating discoveries between basic and clinical labs with several pilot grants, co-mentoring trainees, and multiple jointly authored abstracts, manuscripts, and publications. The four projects and three cores are integrated in their goals and impact such that much more will be achieved together than separately. This PPG utilizes a range of approaches to investigate in-depth molecular mechanisms of ELS-induced hypertension and vascular disease risk as well as to delineate protective factors mediating resiliency to this risk. The results will have important translational potential pointing to new intervention or prevention strategies for the health consequences of CVD and reducing the healthcare burden of CVD.

总体总结 早期生活压力（ELS）被定义为压力和创伤事件，例如家庭功能障碍、忽视、 性虐待或身体虐待、经济困难以及遭受暴力的经历长达 18 年。 ELS 是 20 多年前就被确定为心血管疾病 (CVD) 危险因素，但对其影响的机制尚无深入了解 仍然非常有限。在美国，接触 ELS 的现象非常普遍，约 50% 的儿童和青少年都曾接触过 ELS 或更多主要的 ELS 经历。 ELS 暴露会增加传统 CVD 风险因素的风险 - 3-4 日 十年的人生。最近对欧洲和北美医疗保健负担的分析将 7,480 亿美元归因于 ELS 影响的年度成本，其中 75% 的成本发生在多次 ELS 暴露的人群中。这 我们工作的重要性与 NHLBI 促进心血管疾病预防和治疗的使命是一致的 疾病可以增强所有人的健康，从而延长寿命并过上充实的生活。在有历史的个体中 ELS 暴露、血管功能障碍（外周血管阻力升高、血管硬度增加） 舒张压升高在成年早期就已经很明显了。我们计划的总体目标 项目拨款 (PPG) 旨在定义 ELS 导致 CVD 风险的机制并为预防策略提供信息 以及对暴露于 ELS 的个体的 CVD 后果进行有效治疗。该 PPG 将解决两个关键问题 实现我们目标的障碍：1）需要针对 ELS 进行深入的机制和转化研究；以及，2) 识别 可改变的保护因素，可以降低 ELS 诱发的 CVD 风险。我们 PPG 的总体假设是 ELS 诱导免疫细胞激活，导致血管功能障碍，增加高血压风险， CVD 风险因晚年压力因素而加剧，或因弹性/保护因素而减轻。这个 PPG 与 基础科学和临床项目都采用协同和综合的方法来翻译概念 与人类临床相关的啮齿动物模型。我们的团队极具协同性，每位领导者都带来独特的 来自不同科学背景的专业知识专注于我们了解 ELS 机制的总体目标 CVD 风险和恢复力的诱导指标。在过去的几年里，我们的团队建立了强有力的合作 通过多项试点资助、共同指导学员，在基础实验室和临床实验室之间转化发现 多份共同撰写的摘要、手稿和出版物。四个项目、三个核心分别是 整合他们的目标和影响，这样共同取得的成就比单独取得的成就要多得多。这个PPG 利用一系列方法深入研究 ELS 诱发高血压的分子机制 血管疾病风险以及描述介导这种风险弹性的保护因素。结果将 具有重要的转化潜力，指向新的健康干预或预防策略 CVD 的后果以及减轻 CVD 的医疗负担。