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.