Neurogenomic Investigations of Trichotillomania and Excoriation Disorder

拔毛癖和抓毛障碍的神经基因组学研究

• 批准号: 10599922
• 负责人: Emily Hunt Olfson
• 金额: $ 19.39万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599922
• 关键词: Area; Award; Behavior Therapy; Biological; Biology; Brain; Candidate Disease Gene; Child; Child Rearing; Copy Number Polymorphism; DNA Damage; DNA Sequence; DNA sequencing; Data; Development; Disease; Distress; Ensure; Excoriation; First Degree Relative; Genes; Genetic; Genetic Risk; Genomic approach; Genomics; Gilles de la Tourette syndrome; Glutamates; Goals; Hair; Hour; Individual; Inherited; Intervention; Investigation; Knowledge; Mentors; Mutation; Neurobiology; Obsessive-Compulsive Disorder; Organoids; Outcome; Parents; Pathway Analysis; Pathway interactions; Patients; Pattern; Physicians; Population; Public Health; Publishing; Recurrence; Research; Research Personnel; Risk; Role; Scientist; Series; Skin; Synapses; Systems Analysis; Techniques; Testing; Training; Trichotillomania; Variant; Work; autism spectrum disorder; brain cell; career; cohort; comparison control; de novo mutation; differential expression; effective therapy; excitatory neuron; exome; exome sequencing; experience; functional disability; gene network; genetic variant; genome-wide; genome-wide analysis; improved; induced pluripotent stem cell; inhibitory neuron; innovation; insight; medical complication; multidisciplinary; neural; neurogenetics; neurogenomics; neuropsychiatry; neurotransmission; novel; pharmacologic; programs; repetitive behavior; risk variant; sex; single-cell RNA sequencing; skills; success; transcriptomics; variant detection

PROJECT SUMMARY/ABSTRACT Trichotillomania (hair pulling) and excoriation (skin picking) disorder are debilitating, difficult-to-treat obsessive-compulsive disorder (OCD) spectrum conditions with no first-line pharmacologic interventions. Previous work supports the role of shared genetic factors in the development of these body-focused repetitive behaviors (BFRBs), but progress in identifying BFRB risk genes and biological pathways has been slow. The scientific objective of this K08 award application is to use a series of complementary, unbiased state-of-art neurogenetic approaches to advance our understanding of the genes and pathways that underly BFRBs, which is an important step towards developing improved treatments. Completion of this K08 proposal will provide Dr. Olfson with critical new training in several key areas to achieve her long-term career goal of becoming an independent investigator in neurogenomics. Our central hypothesis is that damaging DNA sequence and structural variants are enriched in individuals with BFRBs compared to controls, and iSPC brain organoids can shed light on convergent neurodevelopmental mechanisms. Guided by strong preliminary data generated by Dr. Olfson from whole-exome DNA sequencing (WES) in BFRB parent-child trios, this hypothesis will be examined in 3 specific aims. In Aim 1, we propose expanding our BFRB cohort to conduct WES in 200 parent-child trios. We will (i) compare de novo and rare inherited WES mutation rates between case and control trios, (ii) examine shared sequence variant genetic risk across the OCD spectrum using 400 previously sequenced OCD trios, and (iii) integrate systems analyses to identify biologic pathways, gene networks, and expression patterns. In Aim 2, Dr. Olfson will develop new skills in analyzing copy-number variants (CNVs) by conducting the first genome-wide CNV study of BFRB parent-child trios. We will (i) compare the de novo and rare inherited CNV burden in the BFRB and control trios, (ii) examine CNVs across the OCD spectrum, and (iii) integrate CNV data with results from Aim 1 for recurrence and enrichment in systems analyses. In Aim 3, Dr. Olfson will expand her skill set in iPSC brain organoids to assess early neurodevelopmental mechanisms of BFRBs. We will characterize iPSC brain organoids derived from 4 patients and unaffected sex-matched first- degree relatives to compare (i) neural differentiation and (ii) transcriptomics by single-cell RNA-sequencing. Overall, this K08 proposal will not only improve our fundamental knowledge of BFRB neurobiology, but also provide Dr. Olfson with vital training necessary to develop an independent neurogenomics research program to continue her investigations of BFRBs and other neuropsychiatric conditions. This training plan involves a multi-disciplinary mentoring team based primarily at the Yale Child Study Center with expertise in genomics (Dr. Fernandez and Dr. Scharf), iSPC brain organoids (Dr. Vaccarino and Dr. Fernandez), and BFRBs (Dr. Bloch and Dr. Scharf). Collectively, these mentors will provide Dr. Olfson with guidance and support to ensure her success in becoming an independent physician-scientist in translational neurogenomics.

项目摘要/摘要 Trichotillomania（拉毛）和挖掘（皮肤采摘）疾病令人衰弱，难以治疗 强迫症（OCD）频谱条件没有一线药理干预措施。 以前的工作支持共享遗传因素在这些以身体重复性的发展中的作用 行为（BFRB），但是鉴定BFRB风险基因和生物途径方面的进展速度很慢。 该K08奖项申请的科学目标是使用一系列补充，公正 最先进的神经遗传学方法来促进我们对基因和途径的理解 BFRB，这是朝着改进的治疗方法迈出的重要一步。完成此K08建议 将为奥尔夫森博士提供在几个关键领域的重要新培训，以实现她的长期职业目标 成为神经基因组学领域的独立研究者。我们的中心假设是破坏性的DNA 与对照组相比，序列和结构变体富含BFRB的个体 器官可以阐明收敛的神经发育机制。以强大的初步数据为指导 该假设由BFRB亲子三重奏中的全异位DNA测序（WES）的Olfson博士生成 将在3个特定目标中进行检查。在AIM 1中，我们建议扩大BFRB队列以进行200个 亲子三重奏。我们将（i）比较从头开始和罕见的案件之间的WES突变率 控制三重奏，（ii）使用先前的400 测序的OCD三重奏和（iii）整合系统分析以识别生物学途径，基因网络和 表达模式。在AIM 2中，Olfson博士将开发新的技能，以分析复制名称变体（CNV） 进行了BFRB亲子三重奏的首次全基因组CNV研究。我们将（i）比较从头和 BFRB和控制三重奏中的罕见遗传CNV负担，（ii）检查OCD频谱的CNV和（iii） 将CNV数据与AIM 1的结果集成在一起，以复发和富集系统分析。在AIM 3中，博士 Olfson将扩大其在IPSC脑器官中的技能，以评估早期神经发育机制 BFRBS。我们将表征来自4例患者的IPSC脑器官，并且不匹配的性别匹配的第一 与单细胞RNA测序相比，程度相关（i）神经分化和（ii）转录组学。 总体而言，这项K08提案不仅会提高我们对BFRB神经生物学的基本知识，而且还可以提高我们的基本知识 还为Olfson博士提供了开发独立神经基因组学研究所需的重要培训 计划继续她对BFRB和其他神经精神疾病的调查。这个培训计划 涉及一个多学科指导团队，主要基于耶鲁儿童学习中心，并具有专业知识 Genomics（Fernandez博士和Scharf博士），ISPC脑器官（Vaccarino博士和Fernandez博士），以及 BFRBS（Bloch博士和Scharf博士）。总的来说，这些导师将为奥尔夫森博士提供指导，并 支持她成功成为转化神经基因组学领域的独立医师科学家。