Genetic Dissection of Restricted Repetitive Behavior (RRB)

描述（由申请人提供）：本K23申请的目的是培养候选人的科学发展和临床研究技能。候选人接受过精神病学/儿童精神病学的结构化临床培训，并接受过艾德库克博士的研究培训，研究儿童期发作的精神疾病的分子遗传基础。候选人将通过独特的整合来自不同资源的专业知识和定制的职业发展计划来扩展她的研究技能。 该研究计划的重点是调查限制性重复行为（RRB）的遗传基础。RRB是描述各种异常重复行为的术语（例如，刻板印象、重复形式的自我伤害行为、强迫症、强迫、仪式化行为、千篇一律的行为和有限的兴趣）。RRB是自闭症谱系障碍（ASD）的核心特征之一，也常见于Prader-Willi综合征（PWS）。RRB经常支配受影响个体的日常活动，干扰发展功能行为的机会，需要干预和治疗。尽管RRB具有重要的功能意义，但其潜在的遗传机制却知之甚少。 在K23申请中，候选人建议检查染色体15 q11-q13区域内的遗传变异，并测试遗传变异与RRB特定形式之间的关联， 患有PWS的人和患有ASD的儿童。该项目的长期目标是了解RRB在临床类别中的常见神经生物学机制。候选人在临床精神病学和分子遗传学方面的培训背景为这项工作提供了良好的基础。 职业发展计划旨在通过以下方式培养候选人的研究技能：（1）Mark刘易斯、Dan Drivel和艾德Cook博士的指导，他们分别在RRB/动物模型、PWS/基因组印记和自闭症/分子遗传学方面具有专长;（2）自闭症、PWS和RRB评估方面的专门培训;（3）与统计遗传学和高通量SNP基因分型专家进行咨询;（4）包括研究设计、数据分析、流行病学和伦理学在内的学科的正式教学培训;（5）出席科学会议并在会议上发言;（6）拟议的研究。鉴于她之前的培训，建议的导师和优秀的资源，这个K23奖将允许候选人成为神经发育遗传性疾病领域的独立临床研究者。 我们的最终研究目标是确定两种临床实体中限制性重复行为（RRB）的遗传因素：自闭症谱系障碍（ASD）和普拉德-威利综合征（PWS）。因此，这项研究的积极结果应该为这些慢性和破坏性临床疾病患者的RRB发病机制和新的治疗方法提供有价值的见解。

DESCRIPTION (provided by applicant): The purpose of this K23 application is to foster scientific development and clinical investigational skills of the candidate. The candidate has had structured clinical training in psychiatry/child psychiatry and research training with Dr. Ed Cook studying molecular genetic bases of childhood-onset psychiatric disorders. The candidate will expand her research skills through a unique integration of expertise from diverse resources and customized career development plan. The research plan focuses on investigation of genetic underpinnings of restricted repetitive behavior (RRB). RRB is a term to describe a wide variety of abnormal repetitive behavior (e.g., stereotypy, repetitive forms of self-injurious behavior, obsession, compulsion, ritualistic behavior, sameness behavior and restricted interests). RRB is one of the core features of autism spectrum disorders (ASDs) and is also commonly observed in Prader-Willi syndrome (PWS). RRB frequently dominates daily activities of affected individuals, interferes with opportunities to develop functional behaviors, and requires intervention and treatment. Despite functional significance of RRB, little is known about underlying genetic mechanism. In this K23 application, the candidate proposes to examine genetic variations within the chromosome 15q11-q13 region and to test association between genetic variants and specific forms of RRB among individuals with PWS and children with ASD. The long-term goal of this project is to understand the common neurobiological mechanism for RRB across the clinical categories. The candidate's training background in clinical psychiatry and molecular genetics provides an excellent foundation for this work. The Career Development Plan is designed for the candidate to develop her research skills by (1) the mentorship of Drs. Mark Lewis, Dan Driscoll, and Ed Cook, who have expertise in RRB/animal models, PWS/genomic imprinting, and autism/molecular genetics, respectively; (2) specific training in assessments of autism, PWS, and RRB; (3) consultation with experts in statistical genetics and high-throughput SNP genotyping; (4) formal didactic training in disciplines including study design, data analysis, epidemiology, and ethics; (5) attendance and presentation in scientific meetings, and (6) the proposed study. Given her prior training, proposed mentorship, and outstanding resources, this K23 Award will permit the candidate to become an independent clinical investigator in the field of neurodevelopmental genetic disorders. PUBLIC HEALTH RELEVANCE Our ultimate research aim is to identify genetic factors for restricted repetitive behavior (RRB) across two clinical entities: autism spectrum disorders (ASDs) and Prader-Willi syndrome (PWS). Therefore, positive results from this study should provide valuable insights into pathogenesis and novel treatment of RRB among individuals with these chronic and devastating clinical conditions.