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.

总体汇总 早期生活压力（ELS）被定义为压力和创伤性事件，如家庭功能障碍，忽视， 遭受性虐待或身体虐待、经济困难和遭受暴力，最长可达18年。埃尔斯 在20多年前就被确定为心血管疾病（CVD）的危险因素，但对其影响的机械见解 仍然非常有限。在美国，ELS的暴露很普遍，约50%的儿童和青少年患有ELS 或更多的ELS经验。ELS暴露会增加传统CVD风险因素的风险-第3 - 4天 几十年生命。最近一项对欧洲和北美医疗保健负担的分析显示， ELS效应的年度成本，其中75%的成本发生在多次暴露于ELS的人群中。的 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一致 疾病，增强所有人的健康，使他们活得更长，生活更充实。在那些有过 ELS暴露、血管功能障碍（外周血管阻力升高、血管僵硬度增加） 和舒张压升高在成年早期已经很明显。我们计划的总体目标 项目补助金（PPG）旨在确定ELS导致CVD风险的机制，并为预防策略提供信息 和有效治疗暴露于ELS的个体的CVD后果。该PPG将解决两个关键问题 实现我们目标的障碍：1）需要ELS特定的深入机制和转化研究; 2）确定 可改变的保护因素，可以降低ELS诱导的CVD风险。我们PPG的首要假设是 ELS诱导免疫细胞活化，导致血管功能障碍，增加高血压风险， 心血管疾病的风险加剧了以后的生活压力或缓和的弹性/保护因素。PPG与 基础科学和临床项目都利用协同和综合的方法， 临床相关的啮齿动物模型。我们的团队是非常协同，每个领导者带来独特的 来自不同科学背景的专业知识集中在我们的总体目标，以了解ELS的机制 心血管疾病风险和弹性的诱导指标。在过去的几年里，我们的团队建立了强大的合作关系， 通过几个试点赠款，在基础和临床实验室之间翻译发现，共同指导学员， 多篇共同撰写的摘要、手稿和出版物。四个工程三个核心是 将其纳入目标和影响中，这样，共同努力将比单独努力取得更多的成果。该PPG 利用一系列方法深入研究ELS诱导的高血压的分子机制， 血管疾病的风险，以及描绘保护因素介导的弹性，这种风险。结果将 具有重要的转化潜力，指向新的干预或预防战略， 心血管疾病的后果和减少心血管疾病的医疗负担。