Early Life Stress Induced Mechanisms of Cardiovascular Disease Risk and Resilience

总体总结 早期生活压力(ELS)被定义为应激性和创伤性事件，如家庭功能障碍、疏忽、 性虐待或身体虐待、经济困难和接触暴力，经历了长达18年的时间。ELS是 20多年前被确定为心血管疾病(CVD)的危险因素，但对其影响的机械洞察力 仍然非常有限。在美国，接触ELS的情况很普遍，约50%的儿童和青少年患有ELS 或更多重要的ELS经验。ELS暴露增加传统心血管疾病风险因素的风险-3-4 十年的生命。最近对欧洲和北美医疗负担的分析将7480亿美元归因于 ELS影响的年度成本，其中75%的成本发生在多次接触ELS的人身上。这个 我们的工作意义与NHLBI促进心血管疾病预防和治疗的使命相一致 疾病增强了所有人的健康，使他们活得更长，活得更充实。在有历史的个人中 ELS暴露，血管功能障碍(外周血管阻力升高，血管僵硬增加) 舒张压升高在成年初期就已经很明显了。我们节目的总体目标是 项目资助(PPG)是定义ELS导致心血管疾病风险的机制，并为预防策略提供信息 以及对暴露于ELS的个人的心血管后果进行有效治疗。这一PPG将解决两个关键问题 实现我们目标的障碍：1)需要专门针对ELS的深入机制和翻译研究；以及，2)确定 可修改的保护因素，可降低ELS诱导的心血管疾病风险。我们的PPG的首要假设是 ELS诱导免疫细胞激活，导致血管功能障碍，高血压风险增加， 因晚年生活应激源而加剧或因复原力/保护性因素而缓和的心血管疾病风险。这个PPG与 基础科学和临床项目都采用协同和综合的方法，将概念从 临床上与人类相关的啮齿动物模型。我们的团队非常具有协作性，每个领导者都带来了独特的 来自不同科学背景的专业知识集中在我们了解ELS机制的总体目标上 心血管疾病风险和复原力的诱导指标。在过去的几年里，我们的团队建立了强大的合作 利用几项试点拨款在基础实验室和临床实验室之间转化发现，共同指导学员，以及 多篇共同撰写的摘要、手稿和出版物。这四个项目和三个核心是 将它们的目标和影响结合起来，以便共同实现的成果将比单独实现的成果更多。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调节对这种风险的复原力的保护性因素。结果将会是 具有重要的翻译潜力，为健康提供新的干预或预防策略 心血管疾病的后果和减轻心血管疾病的医疗负担。

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.