Mouse models of neuroprotection in dopamine neurons

多巴胺神经元神经保护的小鼠模型

• 批准号: 8456168
• 负责人: Eric J Huang
• 金额: $ 14.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456168
• 关键词: Address; Affect; Animal Model; Apoptosis; Award; Biology; Cell Cycle Progression; Cell Death; Clinical; Development; Family; Gene Targeting; Genetically Engineered Mouse; Goals; Human Genetics; Internal Ribosome Entry Site; Lead; Life; Longevity; Maintenance; Mentors; Midbrain structure; Mus; Mutant Strains Mice; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Parkinson Disease; Pathway interactions; Patients; Phenotype; Phosphotransferases; Postdoctoral Fellow; Principal Investigator; Protein Isoforms; Protein Kinase; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Staging; Stem Cell Factor; Students; System; Testing; Time; Training; Training Programs; Transforming Growth Factor beta; Work; cofactor; cytokine; developmental neurobiology; dopaminergic neuron; genetic analysis; homeodomain; in vitro Assay; insight; interdisciplinary approach; member; mouse model; mutant; neurogenesis; neuron loss; neuropathology; neuroprotection; neurotrophic factor; new therapeutic target; postnatal; progenitor; therapeutic target

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 TGFbeta and its downstream signaling kinase HIPK2 support the survival of midbrain DA neurons. Targeted deletion of TGFbeta3 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 TGFbeta2 and TGFbeta3 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 TGFbeta-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 TGFbeta 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.

描述（由申请人提供）：候选人是董事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。在他的整个训练中，他都应用了基因工程小鼠，以研究神经系统中编程细胞死亡中的血肿和神经营养因子中C-KIT配体（干细胞因子）的生物学。自从成为首席研究员以来，申请人将其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。该奖项将保护申请人免受临床和行政责任。它还将使他花费大量时间来开发小鼠模型来保护DA神经元并指导新的研究者在小鼠病理生物学研究中。该奖项赞助的正式指导计划包括：1）建立一个校园范围内的老鼠病理学指导/培训计划，该计划涉及基因工程小鼠（GEM）的基本用途； 2）使用GEM作为模型生物建立在Daergic系统上的微型培训计划。该奖项提出的研究计划是基于最近的发现，即TGFBETA及其下游信号激酶HIPK2支持中脑DA神经元的生存。 TGFBETA3或HIPK2的靶向缺失导致凋亡增加，并且在发育过程中编程细胞死亡期间，DA神经元的显着丧失。有趣的是，我们最近的结果表明，HIPK1和HIPK2在发育的早期阶段都在腹中脑中表达。更重要的是，TGFBETA2和TGFBETA3或HIPK1和HIPK2的同时丧失会导致类似的表型，并且在中脑DA神经元的早期发育中具有更大的障碍。这些结果使我们提出了这样一个假设，即TGFBETA-IHIPK信号通路提供了强大的营养因子支持，可以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检验该假设。这项研究的结果将提供第一个证据，即不同的TGFBETA同工型及其相关的下游信号通路协同起作用，以调节DA神经元在整个寿命中的开发和维持的各个方面。我们的长期目标是将这些突变体的信息用作平台，以确定可以在神经退行性条件下促进DA神经元生存的治​​疗靶标。