Mouse models of neuroprotection in dopamine neurons

应聘者描述(申请人提供)：应聘者是具有发育神经生物学高级研究背景的委员会认证的神经病理学家。在他的整个训练过程中，他应用基因工程小鼠来研究c-kit配体(干细胞因子)在血液生成中的生物学，以及神经营养因子在神经系统细胞程序性死亡中的生物学。自从成为首席研究员以来，申请者将他在老鼠遗传学和人类神经病理学方面的专业知识应用于指导学生和博士后研究员。这项裁决将保护申请人免除临床和行政责任。这也将使他能够投入更多的时间来开发保护DA神经元的小鼠模型，并指导小鼠病理生物学研究中的新研究人员。由该奖项赞助的正式指导计划包括：1)建立校园范围内的小鼠病理生物学指导/培训计划，以解决基因工程小鼠(GEM)的基本用途；以及2)建立以GEM为模式生物的DAR能系统的微型课程培训计划。为该奖项提出的研究计划建立在最近的发现基础上，即转化生长因子及其下游信号激酶HIPK2支持中脑DA神经元的生存。靶向缺失转化生长因子β3或HIPK2导致细胞凋亡增加，在发育过程中细胞程序性死亡期间，DA神经元显著丧失。有趣的是，我们最近的结果表明，HIPK1和HIPK2在发育早期的腹侧中脑中都有表达。更重要的是，同时缺失转化生长因子β2和转化生长因子β3或HIPK1和HIPK2会导致类似的表型，但在中脑DA神经元的早期发育中会出现更明显的缺陷。这些结果使我们假设，转化生长因子β-HIPK信号通路提供了强大的营养因子支持，以一种阶段依赖的方式调节中脑DA神经元的神经发生、存活和成熟。我们提出了几个小鼠模型来检验这一假设。这项研究的结果将提供第一个证据，证明不同的转化生长因子β亚型及其相关的下游信号通路协同工作，在DA神经元整个生命周期中调节其发育和维持的各个方面。我们的长期目标是利用来自这些突变体的信息作为平台，确定可以促进DA神经元在神经退行性变条件下存活的治疗靶点。 帕金森氏症是第二种最常见的神经退行性疾病，在美国有超过150万患者受到影响。在这项研究中，我们建议产生转化生长因子基因缺陷的小鼠突变体。 HIPK2信号转导通路以及该通路如何调节DA神经元的存活和细胞死亡。我们的结果将为确定帕金森病的新治疗靶点提供重要的见解。

DESCRIPTION (provided by applicant): The candidate is a board-certified neuropathologist with advanced research background in developmental neurobiology. Throughout his training, he has applied genetically engineered mice to investigate the biology of c-kit ligand (stem cell factor) in hematopiesis and neurotrophic factors in programmed cell death in the nervous system. Since becoming a principal investigator, the applicant has applied his expertise in mouse genetics and human neuropathology to mentoring students and postdoctoral fellows. This award will protect the applicant from clinical and administrative responsibilities. It will also allows him to devote a greater amount of time to develop mouse models for protecting DA neurons and to mentoring new investigators in mouse pathobiology research. The formal mentoring plans sponsored by this award include: 1) Establish a campus-wide mouse pathobiology mentoring/training program that addresses the fundamental uses of genetically engineered mice (GEM); and 2) Establish a minicourse training program on the DAergic system using GEM as a model organism. The research plans proposed for this award are built on recent findings that TGF¿ and its downstream signaling kinase HIPK2 support the survival of midbrain DA neurons. Targeted deletion of TGF¿3 or HIPK2 leads to increased apoptosis and a significant loss of DA neurons in the period of programmed cell death during development. Intriguingly, our recent results show that both HIPK1 and HIPK2 are expressed in ventral midbrain during early stages in development. More importantly, simultaneous loss of TGF¿2 and TGF¿3 or HIPK1 and HIPK2 leads to similar phenotype with even more robust deficits in the early development of midbrain DA neurons. These results lead us to the hypothesis that TGF¿-HIPK signaling pathway provides robust trophic factor support that regulates neurogenesis, survival and maturation of midbrain DA neurons in a stage-dependent fashion. We propose several mouse models to test this hypothesis. Results from this study will provide the first evidence that different TGF¿ isoforms and its associated downstream signaling pathways work in concert to regulate various aspects of the development and maintenance of DA neurons during its entire life span. Our long-term goal is to use information from these mutants as platforms to identify therapeutic targets that can promote survival of DA neurons under neurodegenerative conditions. Parkinson's disease is the second most common neurodegenerative disease that affects more than 1.5 million patients in US. In this study, we propose to generate mouse mutants that are defective in TGF¿- HIPK2 signaling and to characterize how this pathway regulates survival and cell death in DA neurons. Our results will provide important insights to identifying novel therapeutic targets for Parkinson's disease.