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: 10348265
• 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/10348265
• 关键词: Area; Award; Behavior Control; Behavior Therapy; Biological; Biology; Brain; Candidate Disease Gene; Child; 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; Lead; Light; Medical; Mentors; Mutation; Neurobiology; Obsessive-Compulsive Disorder; Organoids; Outcome; Parents; Pathway Analysis; Pathway interactions; Patients; Pattern; Pharmacology; Physicians; Public Health; Publishing; Recurrence; Research; Research Personnel; Risk; Role; Scientist; Series; Skin; Synapses; Systems Analysis; Techniques; Testing; Training; Trichotillomania; Variant; Work; base; brain cell; career; case control; cohort; 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; multidisciplinary; neurogenetics; neurogenomics; neuropsychiatry; neurotransmission; novel; programs; relating to nervous system; 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.

项目总结/摘要 拔毛症（拔毛）和表皮剥脱症（皮肤采摘）是使人衰弱的，难以治疗的 强迫症（OCD）谱系疾病，无一线药物干预。 以前的工作支持共享的遗传因素在这些以身体为中心的重复性发育中的作用。 然而，在确定BFRB风险基因和生物学途径方面的进展一直很缓慢。 这个K 08奖项申请的科学目标是使用一系列互补的，无偏见的 最先进的神经遗传学方法，以促进我们对基因和途径的理解， BFRBs，这是朝着开发更好的治疗方法迈出的重要一步。完成K 08提案 将在几个关键领域为Olfson博士提供关键的新培训，以实现她的长期职业目标， 成为神经基因组学的独立研究者我们的核心假设是， 与对照组相比，BFRB个体的序列和结构变异富集，iSPC脑 类器官可以揭示收敛神经发育机制。以强有力的初步数据为指导 由Olfson博士从BFRB亲子三人组的全外显子组DNA测序（WES）中产生， 将在三个具体目标中进行研究。在目标1中，我们建议扩大我们的BFRB队列，以在200年进行WES 亲子三人组我们将（i）比较病例和对照组之间的新发和罕见遗传性WES突变率， 对照三人组，（ii）使用400个先前的基因序列检查OCD谱中的共享序列变异遗传风险 测序的OCD trios，和（iii）整合系统分析，以确定生物途径，基因网络， 表达模式在目标2中，Olfson博士将通过以下方式开发分析拷贝数变异（CNVs）的新技能： 进行了第一个全基因组范围的BFRB亲子三人组CNV研究。我们将（i）比较从头开始， 在BFRB和对照三人组中罕见的遗传性CNV负担，（ii）检查OCD谱中的CNV，和（iii） 将CNV数据与目标1的结果相结合，以便在系统分析中重现和富集。在目标3中，博士 Olfson将扩展她在iPSC脑类器官方面的技能，以评估 BFRB。我们将首先表征来自4名患者和未受影响的性别匹配的iPSC脑类器官- 通过单细胞RNA测序比较（i）神经分化和（ii）转录组学。 总的来说，K 08的提案不仅将提高我们对BFRB神经生物学的基础知识， 还为Olfson博士提供了开展独立神经基因组学研究所需的重要培训 继续她对BFRB和其他神经精神疾病的调查。本培训计划 涉及一个多学科的指导团队，主要设在耶鲁大学儿童研究中心，具有以下方面的专业知识： 基因组学（费尔南德斯博士和Scharf博士），iSPC脑类器官（Vaccarino博士和费尔南德斯博士），以及 BFRB（Bloch博士和Scharf博士）。总的来说，这些导师将为Olfson博士提供指导， 支持确保她成功成为转化神经基因组学领域的独立医生兼科学家。