Behavior in Mouse Tryptophan Hydroxylase Mutants

应聘者描述(申请人提供)：应聘者为儿童和青少年精神病学家，具有分子生物学和神经科学的经验。他拥有终身教职，在密歇根大学医学中心有80%的研究时间。这一职业发展奖将有助于扩大他的技能，包括开发遗传动物模型及其行为表型。该技能基础与密歇根大学精神卫生研究所(MHRI)的承诺交织在一起，该研究所承诺应用新的分子方法来确定严重抑郁症的新候选基因，并进行它们的解剖、结构和功能表征。预计到这笔拨款结束时，候选人将获得足够的经验，并为独立研究和合作创造了几个有信息的动物模型。密歇根大学医学中心是一个蓬勃发展的研究社区，拥有开展拟议研究的充足资源。一个非常成功的核心设施可用于转基因操作。MHRI的教员拥有基因工程、生物化学、啮齿动物解剖学和动物行为领域的专业知识。这位候选人由MHRI的一名高级研究科学家监督，并得到了老鼠转基因和行为表型领域领导人的咨询支持。这个项目应用新兴的分子技术来扩大对5-羟色胺生物合成和神经递质水平在神经系统发育和行为中的作用的理解。该设计使用神经元特异性和四环素诱导的遗传元素来设计转基因小鼠，允许调节色氨酸羟基酶(TPH)的活性。TPH是5-羟色胺生物合成的限速酶，因此对5-羟色胺的转化至关重要。重组动物将允许探测大脑5-羟色胺的时间和组织选择性上调或下调对焦虑、注意力、学习、记忆、攻击性、食欲、药物偏好和其他行为的影响。这项拟议的研究是情绪和焦虑症的5-羟色胺假说的核心，并为研究5-羟色胺周转对大脑成熟的发育影响提供了一个模型。候选人的长期职业计划是一项学术研究，整合了人类临床、遗传和动物模型信息，用于治疗严重的情绪障碍

DESCRIPTION (provided by applicant): The candidate is a child and adolescent psychiatrist with experience in molecular biology and neuroscience. He holds a tenure track junior faculty appointment with 80 percent research time at the University of Michigan Medical Center. This career development award will serve to expand his skills to include the development of genetic animal models and their behavioral phenotyping. The skill base interdigitates with a commitment by the University of Michigan Mental Health Research Institute (MHRI) to apply novel molecular approaches to identify new candidate genes for major depression and undertake their anatomic, structural, and functional characterizations. It is expected that by the end of this grant, the candidate will have gained sufficient experience and generated several informative animal models for independent research and collaboration. The University of Michigan Medical Center is a thriving research community with ample resources for carrying out the proposed studies. A highly successful core facility is available for transgenic manipulation. Faculty in the MHRI bear expertise in the areas of genetic engineering, biochemistry, rodent anatomy, and animal behavior. The candidate is being supervised by a senior research scientist in the MHRI with consultative support from leaders in the field of mouse transgenics and behavior phenotyping. This project applies emerging molecular technology to expand understanding on the role of serotonin biosynthesis and neurotransmitter levels on nervous system development and behavior. The design employs neuron specific and tetracycline-inducible genetic elements to engineer transgenic mice permitting regulation of tryptophan hydroxylase (TPH) activity. TPH is the rate-limiting enzyme in serotonin biosynthesis, and is thereby critical to serotonin turnover. The recombinant animals will permit probing the effects of temporal and tissue-selective up- or down-regulation of brain serotonin on measures of anxiety, attention, learning, memory, aggression, appetite, drug preference, and other behaviors. The proposed research is central to the serotonin hypothesis of mood and anxiety disorders, and offers a model for studying the developmental effects of serotonin turnover on brain maturation. The candidate's long-term career plan is academic research integrating human clinical, genetic and animal model information for major mood disorders