Murine Genetic Models of Autism

自闭症小鼠遗传模型

基本信息

批准号：
7904037
负责人：
Jeremy Veenstra-VanderWeele
金额：
$ 17.24万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-13 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7904037
关键词：
Affect Amino Acids Autistic Disorder Behavior Behavioral Binding Biochemical Blood Platelets Brain Breeding Carrier Proteins Cell surface Child Child Psychiatry Clinical Collaborations Data Development Family Functional disorder Funding Genes Genetic Genetic Determinism Genetic Models Genetic Polymorphism Genotype Goals Human ITGB3 gene Integrins Knock-in Mouse Knockout Mice Laboratories Lead Learning Mentors Methodology Modeling Molecular Molecular Genetics Mus Mutation Neurosciences Neurotransmitters Obsessive compulsive behavior Obsessive-Compulsive Disorder Pathway interactions Phenotype Postdoctoral Fellow Predisposition Prevention strategy Process Production Proteins Psychiatrist Psychiatry Research Research Personnel Research Training Serotonin Signal Transduction Specialist Syndrome System Techniques Training Training Programs Transgenic Mice Transgenic Organisms Variant autism spectrum disorder brain morphology career development graduate student indexing interest monoamine programs protein protein interaction receptor binding serotonin receptor serotonin transporter skills social somatosensory trait

项目摘要

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.

描述（由候选人提供）：该提案概述了一个五年的计划，以培训儿童精神病医生研究自闭症的分子病理生理学。自闭症谱系障碍影响160名儿童中多达1个。关于自闭症病理生理学，限制治疗和预防策略的遗传决定因素知之甚少。候选人已经完成了儿童精神病学和人分子遗传学研究培训的临床培训。他建议学习一组新的科学技能，以使用转基因小鼠在自闭症中对5-羟色胺系统的改变。培训计划以分析大脑和血小板5-羟色胺系统的技术为中心，以及研究导致小鼠脑形态和行为变化的方法。最近的遗传和生化研究暗示了整联蛋白33和5-羟色胺转运蛋白基因的遗传和物理相互作用在血小板5-羟色胺水平以及自闭症特征的测定中。候选人建议使用转基因小鼠了解这两个基因变异的影响。具体目的包括：1）整联蛋白（33; 2）小鼠表达过度活跃的5-羟色胺转运蛋白425LEU变体的小鼠的大脑和行为分析； 3）整联蛋白P3和5-羟色胺转运蛋白变异的小鼠杂合子，以模拟常见人变异的相互作用效应。候选人的导师兰迪·布拉克利（Randy Blakely）博士是神经递质转运蛋白领域的国际尊敬的研究人员，在候选人感兴趣的领域拥有活跃的，资金丰富的实验室。他在研究单胺转运蛋白的研究中培训了众多研究生和博士后研究员，包括转基因小鼠的生产和表征。为了增加进一步的专业知识，自闭症鼠模型专家Jacqueline Crawley博士将为小鼠行为研究提供建议，Elaine Sanders-Bush博士将就5-羟色胺受体研究建议。范德比尔特（Vanderbilt）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（Vanderbilt）在5-羟色胺系统和对自闭症研究的坚定承诺方面的分子研究集体专业知识为促进候选人的职业发展提供了无与伦比的机会，以制定与儿童精神病学相关的独立研究计划。