Behavior in Mouse Tryptophan Hydroxylase Mutants

描述（由申请人提供）：该候选人是一名具有分子生物学和神经科学经验的儿童和青少年精神病学家。他在密歇根大学医学中心拥有终身教职，有80%的研究时间。这一职业发展奖将有助于扩大他的技能，包括遗传动物模型和他们的行为表型的发展。该技能基础与密歇根大学心理健康研究所（MHRI）的一项承诺相结合，即应用新颖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。预计到资助结束时，候选人将获得足够的经验，并为独立研究和合作生成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，拥有充足的资源来开展拟议的研究。一个非常成功的核心设施可用于转基因操作。MHRI的教师在基因工程、生物化学、啮齿动物解剖学和动物行为学等领域具有专业知识。该候选人由MHRI的一名高级研究科学家指导，并得到小鼠转基因和行为表型领域领导人的咨询支持。该项目应用新兴的分子技术来扩大对血清素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。该设计采用神经元特异性和四环素诱导的遗传元件来设计转基因小鼠，允许调节色氨酸羟化酶（TPH）活性。TPH是5 -羟色胺生物合成中的限速酶，因此对5 -羟色胺的转化至关重要。重组动物将能够探测大脑血清素在焦虑、注意力、学习、记忆、攻击性、食欲、药物偏好和其他行为方面的时间和组织选择性上调或下调调节的影响。该研究是情绪和焦虑障碍的血清素假说的核心，并为研究血清素转换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学术研究，整合人类临床，遗传和动物模型信息的主要情绪障碍

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