This proposal describes a 3 year program to investigate the relations between childhood dysregulation and adult substance abuse, psychopathology, and metabolic syndrome. In this COBRE Project the junior principal investigator, an M.D., Ph.D. with training in child and adolescent psychiatry will work with primary mentor James Hudziak, MD, senior mentors Hugh Garavan, MD and Phil Ades, MD to investigate the metabolic, epigenetic, executive function/decision-making, and psychophysiological mechanisms of a child behavioral syndrome termed "dysregulation." The study proposes that dysregulation is a common prodrome for a variety of negative adult outcomes (substance abuse, persistent psychopathology, and the cluster of non-psychiatric disorders referred to as "Metabolic Syndrome" (MS) - diabetes, dyslipedemia, hypertension, and obesity. We propose a model consisting of environmental impact (e.g., low socioeconomic status, chronic adversity) on a genetic predisposition (e.g., family history of self-regulatory problems) affecting the systems involved in self-regulation. The dysregulatory effects in turn affect gluocorticoid and autonomic nervous system (e.g., heart rate variability) responses. We will test this model through the use of a family study approach. In order to do this work, we propose adding measurement of metabolic, epigenetic, executive function/decision-making, and psychophysiological data to parents of children in an ongoing family study of children with dysregulation (NIMH K08MH082116). Through the course of the 3 year study, we will determine the rates of substance use disorders, psychopathology, and metabolic syndrome in the families of children with dysregulation. We will determine the rates of delay discounting (a measure of impulsivity) and the levels of heart rate variability (a measure of autonomic stability) in these children and their families. Using two complementary methods, we will determine the epigenetic profiles in dysregulated children and their family members in two gene promoters known to be associated withs stress reactivity (NR3C1 and FKBP5).
Determining the mechanisms of how behavioral symptoms can lead to later adult outcomes has the potential to significantly reduce morbidity and mortality. Here, we propose to examine a pattern of poor selfregulation in childhood and predict associations with obesity, hypertension, diabetes, substance abuse, and psychiatric disorders in their families. We predict a mechanism involving genes involved in stress reactivity.
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