Genetic Dissection of Restricted Repetitive Behavior (RRB)

描述(申请人提供)：本次K23申请的目的是培养应聘者的科学发展和临床研究技能。这位候选人曾在精神病学/儿童精神病学方面接受过系统的临床培训，并与埃德·库克博士一起研究儿童精神障碍的分子遗传学基础。应聘者将通过独特的整合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。该研究计划重点调查限制性重复行为(RRB)的遗传基础。RRB是一个术语，用来描述各种各样的不正常的重复行为(例如，刻板的、重复的自我伤害行为、强迫、强迫、仪式性行为、相同的行为和受限的兴趣)。RRB是自闭症谱系障碍(ASDS)的核心特征之一，也是Prader-Willi综合征(PWS)的常见症状。RRB经常支配受影响个体的日常活动，干扰发展功能性行为的机会，需要干预和治疗。尽管RRB具有重要的功能，但人们对其潜在的遗传机制知之甚少。在K23的应用中，候选人建议检查染色体15q11-q13区域内的遗传变异，并测试遗传变异与特定形式的RRB之间的关联 患有PWS的个人和患有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。应聘者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发展候选人的研究技能：(1)分别在RRB/动物模型、PWS/基因组印迹和自闭症/分子遗传学方面拥有专长的Mark Lewis、Dan Driscoll和Ed Cook博士的指导；(2)自闭症、PWS和RRB评估方面的专门培训；(3)咨询统计遗传学和高通量SNP基因分型方面的专家；(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)出席科学会议并发表报告；以及(6)拟议的研究。考虑到她之前的培训，建议的导师和杰出的资源，这个K23奖将允许候选人成为神经发育遗传障碍领域的独立临床研究员。公共卫生相关性我们的最终研究目标是确定两个临床实体的限制性重复行为(RRB)的遗传因素：自闭症谱系障碍(ASDS)和Prader-Willi综合征(PWS)。因此，这项研究的积极结果将为这些慢性和破坏性临床疾病患者的RRB的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.