Murine Genetic Models of Autism

描述(由候选人提供)：这项提案概述了一个五年计划，培训一名儿童精神病学家研究自闭症的分子病理生理学。自闭症谱系障碍影响多达160名儿童中的1名。关于自闭症病理生理学的遗传决定因素、有限的治疗和预防策略知之甚少。候选人已经完成了儿童精神病学的临床培训和人类分子遗传学的同步研究培训。他建议学习一套新的科学技能，使用转基因小鼠来模拟自闭症患者血清素系统的变化。培训计划的中心是分析大脑和血小板5-羟色胺系统的技术，以及研究小鼠大脑形态和行为由此发生的变化的方法。最近的遗传和生化研究表明，整合素33和5-羟色胺转运体基因在决定血小板5-羟色胺水平和自闭症特征方面存在遗传和物理上的相互作用。候选人建议使用转基因小鼠来了解这两个基因变异的影响。具体目标包括：1)整合素表达减少或缺失的小鼠(33)；2)表达过度活跃的5-羟色胺转运体425Leu变异体的小鼠；以及3)整合素p3和5-羟色胺转运体变异体杂合的小鼠，以模拟常见人类变异的相互作用效应。候选人的导师兰迪·布莱克利博士是神经递质转运蛋白领域的国际知名研究员，在候选人感兴趣的领域拥有一个活跃的、资金充足的实验室。他培训了许多研究单胺转运蛋白的研究生和博士后研究员，包括转基因小鼠的生产和特征。为了增加更多的专业知识，自闭症小鼠模型专家杰奎琳·克劳利博士将就小鼠行为研究提供建议，伊莱恩·桑德斯-布什博士将就5-羟色胺受体研究提供建议。范德比尔特大学精神病学系和分子神经科学中心为候选人的发展提供了理想的环境。范德比尔特在5-羟色胺系统分子研究方面的集体专业知识和对自闭症研究的坚定承诺提供了一个无与伦比的机会，可以推动候选人的职业发展，朝着开发与儿童精神病学相关的独立研究项目的目标前进。

DESCRIPTION (provided by candidate): This proposal outlines a five year program to train a child psychiatrist to study the molecular pathophysiology of autism. Autism spectrum disorders affect as many as 1 in 160 children. Little is known concerning the genetic determinants of autism pathophysiology, limiting treatment and prevention strategies. The candidate has completed clinical training in child psychiatry and concurrent research training in human molecular genetics. He proposes to learn a new set of scientific skills to use transgenic mice to model alterations of the serotonin system in autism. The training program centers on techniques to analyze the brain and platelet serotonin system, as well as methodology to study resulting changes in mouse brain morphology and behavior. Recent genetic and biochemical studies implicate genetic and physical interactions of the integrin 33 and serotonin transporter genes in the determination of platelet serotonin levels as well as autism traits. The candidate proposes to use transgenic mice to understand the impact of variation in these two genes. The Specific Aims include brain and behavioral analyses of: 1) Mice with decreased or absent expression of integrin (33; 2) Mice expressing an overactive serotonin transporter 425Leu variant; and 3) Mice heterozygous for both integrin p3 and serotonin transporter variants to model interaction effects of common human variation. The candidate's mentor, Dr. Randy Blakely, is an internationally respected researcher in the field of neurotransmitter transporters and has an active, well-funded laboratory in the candidate's field of interest. He has trained numerous graduate students and postdoctoral fellows in the study of monoamine transporter proteins, including the production and characterization of transgenic mice. To add further expertise, Dr. Jacqueline Crawley, a specialist in murine models of autism, will advise on mouse behavioral studies, and Dr. Elaine Sanders-Bush will advise on serotonin receptor studies. The Department of Psychiatry and the Center for Molecular Neuroscience at Vanderbilt present an ideal setting for the candidate's development. Vanderbilt's collective expertise in molecular research on the serotonin system and strong commitment to autism research provide an unparalleled opportunity to advance the candidate's career development toward the goal of developing an independent research program relevant to child psychiatry.