GENETIC DISSECTION OF AGGRESSIVE BEHAVIORS

描述(申请人提供)：这项建议旨在为Edward S.Brodkin医学博士提供为期五年的监督研究培训，使他能够成为一名独立研究人员，研究重点是小鼠攻击行为的基因解剖。应聘者将在数量性状基因座(QTL)的高分辨率遗传作图、候选基因分析和突变方法方面获得培训和经验。 背景：攻击行为是严重神经精神障碍患者发病率和死亡率的主要来源。哺乳动物的攻击性倾向基本上是可遗传的。对小鼠攻击行为的遗传解剖可以确定哺乳动物攻击行为背后的生物路径，这些路径可能涉及人类精神疾病的病理生理学。Brodkin博士以前在NZB/B1NJ和A/J小鼠中发现了位于10号染色体(Aggr1)和X染色体(Aggr2)上的攻击性QTL；然而，他之前在QTL的高分辨率(精细)定位、候选基因分析或突变方法方面没有经验。这些方法的培训对候选人的职业发展很重要，对他未来的研究独立性也是必要的。 研究计划的具体目标：1.精细定位攻击性QTL。以NZB/B1NJ和AJ小鼠为祖先品系，将培育出Aggr1和Aggr2 QTL区间的区间特异性同源品系，并用于精细定位QTL区间。2.候选基因分析。在精细定位的QTL区间内，在大脑中表达的候选基因将在前体菌株中进行测序，以寻找功能多态。候选基因在脑区的表达水平将在前体菌株中进行比较。3.启动对攻击行为的诱变研究。将启动对小鼠攻击行为的enu突变和基因陷阱研究。 环境：培训将在宾夕法尼亚大学医学院精神病学系神经生物学和行为中心进行。 研究职业发展：应聘者将在宾夕法尼亚大学和其他地方参加相关课程，并参加研究会议。Wade Berrettini博士将担任导师，Maja Bucan博士、Russell Buono博士、Thomas Ferraro博士和Irwin Lucki博士将提供遗传学和行为分析方面的额外咨询。

DESCRIPTION (provided by applicant): This proposal seeks to provide Edward S. Brodkin, M.D. with a five-year period of supervised research training that will enable him to become an independent investigator, with a research focus on the genetic dissection of aggressive behaviors in mice. The candidate will gain training and experience in high resolution genetic mapping of quantitative trait loci (QTLs), candidate gene analysis, and mutagenesis methods. Background: Aggressive behaviors are a major source of morbidity and mortality in patients with severe neuropsychiatric disorders. A propensity towards aggression is substantially heritable in mammals. Genetic dissections of aggressive behaviors in mice can identify biological pathways that underlie mammalian aggression and that may be involved in the pathophysiology of human psychiatric disorders. Dr. Brodkin has previously identified aggression QTLs on chromosome 10 (Aggr1) and chromosome X (Aggr2) in NZB/B1NJ and A/J mice; however he has had no previous experience with high-resolution (fine) mapping of QTLs, candidate gene analysis, or mutagenesis methodologies. Training in these methodologies is important for the candidate's career development and is necessary for his future research independence. Specific Aims of Research Plan: 1. Fine-mapping aggression QTLs. Using NZB/B1NJ and AJ mice as progenitor strains, interval-specific congenic strains will be bred for the Aggr1 and Aggr2 QTL intervals and will be used to fine map the QTL intervals. 2. Candidate gene analysis. Within the finely mapped QTL intervals, candidate genes that are expressed in brain will be sequenced in the progenitor strains to look for functional polymorphisms. Expression level of the candidate genes in brain regions will be compared in the progenitor strains. 3. Initiation of mutagenesis studies of aggressive behaviors. ENU mutagenesis and gene-trap studies of aggressive behaviors in mice will be initiated. ENVIRONMENT: The training will be conducted at the Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania School of Medicine. RESEARCH CAREER DEVELOPMENT: The candidate will take relevant courses at Penn and elsewhere and will attend research meetings. Dr. Wade Berrettini will be the mentor, and Drs. Maja Bucan, Russell Buono, Thomas Ferraro, and Irwin Lucki will provide additional consultation in genetics and behavioral analysis.