Behavior in Mouse Tryptophan Hydroxylase Mutants

描述（由申请人提供）：候选人是一名儿童和青少年精神科医生，在分子生物学和神经科学方面有经验。他在密歇根大学医学中心拥有80%的研究时间的终身教职。这个职业发展奖将有助于扩大他的技能，包括遗传动物模型及其行为表型的发展。该技能库与密歇根大学心理健康研究所（MHRI）的承诺相互交织，以应用新的分子方法来识别新的抑郁症候选基因，并对其进行解剖，结构和功能表征。预计到该补助金结束时，候选人将获得足够的经验，并为独立研究和合作产生几个信息丰富的动物模型。密歇根大学医学中心是一个蓬勃发展的研究社区，拥有充足的资源进行拟议的研究。一个非常成功的核心设施可用于转基因操作。MHRI的教师在遗传工程，生物化学，啮齿动物解剖学和动物行为学领域拥有专业知识。候选人由MHRI的一位高级研究科学家监督，并得到小鼠转基因和行为表型领域领导者的咨询支持。该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对神经系统发育和行为的作用的理解。该设计采用神经元特异性和四环素诱导的遗传元件来设计允许调节色氨酸羟化酶（TPH）活性的转基因小鼠。TPH是5-羟色胺生物合成中的限速酶，因此对5-羟色胺周转至关重要。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。这项研究是情绪和焦虑症的血清素假说的核心，并为研究血清素周转对大脑成熟的发育影响提供了一个模型。候选人的长期职业规划是整合人类临床、遗传和动物模型信息的重大情绪障碍的学术研究

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