Shared Mechanisms in Child Dysregulation, Adult Psychopath, & Metabolic Diso...

项目摘要(见说明)：该提案描述了一项为期3年的计划，旨在调查儿童调节失调与成人药物滥用、精神病理学和代谢综合征之间的关系。在这个Cobre项目中，初级首席研究员，一位接受过儿童和青少年精神病学培训的医学博士和博士，将与医学博士詹姆斯·哈齐亚克、医学博士资深导师休·加拉万和医学博士菲尔·阿德斯合作，研究一种被称为“调节失调”的儿童行为综合征的代谢、表观遗传学、执行功能/决策和心理生理机制。该研究提出，调节失调是各种负面成人后果(药物滥用、持续的精神病理以及被称为“代谢综合征”(MS)的一系列非精神性疾病--糖尿病、血脂异常、高血压和肥胖症)的常见前兆。我们提出了一个模型，包括环境影响(例如，低社会经济地位，长期逆境)对影响自我调节系统的遗传倾向(例如，自我调节问题的家族史)的影响。调节失调效应反过来影响糖皮质激素和自主神经系统(例如，心率变异性)的反应。我们将通过使用家庭研究的方法来测试这个模型。为了做这项工作，我们建议在一项正在进行的关于调节失调儿童的家庭研究中，向儿童的父母增加新陈代谢、表观遗传学、执行功能/决策和心理生理学数据的测量(NIMH K08MH082116)。通过为期3年的研究，我们将确定物质使用障碍、精神病理学和代谢综合征在调节障碍儿童家庭中的发生率。我们将确定这些儿童及其家庭的延迟折扣率(衡量冲动程度)和心率变异性水平(衡量自主神经稳定性)。使用两种互补的方法，我们将确定两个已知与应激反应相关的基因启动子(NR3C1和FKBP5)在调节失调儿童及其家庭成员中的表观遗传学特征。

PROJECT SUMMARY (See instructions): 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).