Epigenetic Response to Early Life Stress and the Impact on Cardiovascular Health

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Childhood adversity, characterized by abuse, neglect and household dysfunction, is a national problem that exerts an enormous impact on individuals, families and society, and is of great significance for public health. Growing evidence suggests that traumatic experiences in childhood are associated with health decline in adulthood, including substance abuse, mental disorders and cardiovascular disease. However, the underlying biological mechanisms remain unclear. Epigenetics, including DNA methylation, plays an important role in gene regulation in response to external environmental signals. This mechanism is of particular relevance for behavioral biology. Recent studies and our preliminary results have found that epigenetics, e.g. DNA methylation, is involved in shaping the endocrine and immune responses to early life social environment. Therefore, we propose that exposure to early life stress (ELS) may modify DNA methylation patterns and these modification are persistent over time leading to increased risk for cardiovascular disease later in life. Since 1989 we have established a longitudinal cohort in which over 600 children have been followed-up 16 times in 22 years. Adverse childhood experiences (ACEs) prior to age 18 has been assessed in these participants, including childhood abuse (e.g. sexual), neglect (e.g. emotional), and growing up with household dysfunction (e.g. substance abuse or domestic violence in family members). Children who were severely exposed to ACEs, i.e. experienced multiple events (e4) during childhood, have developed mental problem and unfavorable vascular and cardiac function detectable in early adulthood. By taking advantage of this well-established longitudinal cohort, we aim to identify ELS-related DNA methylation modifications in early young adulthood and to examine their impacts on cardiovascular health over time. The specific aims of this project are: (1)To identify ELS-related DNA methylation modifications in a 3-step approach: genome-wide screening, cross-visit validating and functional testing; (2) To examine the longitudinal varies of DNA methylation levels in response to ACE exposures and to test whether at-risk behaviors and low socioeconomic status in young adulthood can accelerate this process; (3) To examine the longitudinal contributions of ELS-related methylation modifications to the development of multiple cardiovascular measures over time. This project will lay the groundwork for examining the role of DNA methylation in conferring risk for cardiovascular health in individuals with history of childhood adversity, and identify new etiology indicating how early lif psychological stress becomes "biologically embedded" and influences health outcomes through the life course, which may aid in developing novel prevention and intervention strategies to reduce the burden associated with stress-related health problems.