Mouse models of neuroprotection in dopamine neurons

描述（由申请人提供）：候选人是一名委员会认证的神经病理学家，具有发育神经生物学的高级研究背景。在他的训练中，他应用基因工程小鼠研究造血中c-kit配体（干细胞因子）的生物学和神经系统中程序性细胞死亡中的神经营养因子。自从成为首席研究员以来，申请人将其在小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。该奖项将保护申请人免受临床和行政责任。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的新研究人员。该奖项赞助的正式指导计划包括：1）建立一个全校范围的小鼠病理生物学指导/培训计划，解决基因工程小鼠（GEM）的基本用途; 2）建立一个关于DA能系统的微型课程培训计划，使用GEM作为模型生物。为该奖项提出的研究计划是建立在最近的发现，即TGF β及其下游信号激酶HIPK 2支持中脑DA神经元的存活。靶向删除TGF？3或HIPK 2导致在发育过程中的程序性细胞死亡期间增加的细胞凋亡和DA神经元的显著损失。有趣的是，我们最近的研究结果表明，HIPK 1和HIPK 2在发育的早期阶段在腹侧中脑中表达。更重要的是，TGF <$2和TGF <$3或HIPK 1和HIPK 2的同时缺失导致类似的表型，在中脑DA神经元的早期发育中具有甚至更强的缺陷。这些结果使我们假设TGF-β-HIPK信号通路提供了强大的营养因子支持，以阶段依赖性方式调节中脑DA神经元的神经发生、存活和成熟。我们提出了几种小鼠模型来验证这一假设。这项研究的结果将提供第一个证据表明，不同的TGF β亚型及其相关的下游信号通路协同工作，以调节DA神经元在其整个生命周期中的发育和维持的各个方面。我们的长期目标是利用这些突变体的信息作为平台，以确定可以促进神经退行性疾病条件下DA神经元存活的治疗靶点。 帕金森病是第二大常见的神经退行性疾病，在美国影响超过150万患者。在这项研究中，我们建议产生小鼠突变体，是有缺陷的TGF β- HIPK 2信号通路，并描述该通路如何调节DA神经元的存活和细胞死亡。我们的研究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.