Intermediate Progenitor Cells in Adult Hippocampal Neurogenesis

成人海马神经发生中的中间祖细胞

• 批准号: 7811197
• 负责人: Robert F Hevner
• 金额: $ 53.44万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-20 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7811197
• 关键词: Adult; Affect; Age; Alzheimer' s Disease; Area; Astrocytes; Brain Diseases; Cell Count; Cells; Cerebral Palsy; Cerebrum; Commit; Defect; Development; Disease; Embryo; Employment; Epilepsy; Equipment and Supplies; Foundations; Functional disorder; Gene Silencing; Genetic; Glutamates; Goals; Hippocampus (Brain); Human Resources; Image; Immigration; Intervention; Label; Life; Link; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Nature; Neurodegenerative Disorders; Neurons; Occupations; Parahippocampal Gyrus; Pathogenesis; Pathway interactions; Positioning Attribute; Postdoctoral Fellow; Property; Radial; Recovery; Regulation; Replacement Therapy; Research; Resources; Role; Schizophrenia; Scientist; Slice; Stem cells; Stroke; Testing; Therapeutic; Time; Trauma; addiction; adult neurogenesis; base; cell motility; cell type; cellular imaging; dentate gyrus; depression; design; granule cell; improved; insight; migration; neocortical; nerve stem cell; neurogenesis; neuron loss; neuropsychiatry; parent grant; parent project; postnatal; progenitor; public health relevance; ranpirnase; relating to nervous system; response; retroviral transduction; stem; time use; transcription factor

DESCRIPTION (provided by applicant): This project revision extends our analysis of hippocampal neurogenesis from adulthood, the focus of the parent grant, into postnatal ages in mice. The overall goal of the parent project is to gain greater understanding of adult hippocampal neurogenesis, its mechanisms and regulation. Adult neurogenesis has important implications for designing strategies of neural replacement therapy, which could be used to treat neurodegenerative disorders and other conditions of neuronal loss. The goal of this revision project is to gain insights into postnatal development of the hippocampus, especially the dentate gyrus. Development of the dentate gyrus not only lays the foundation for adult neurogenesis, but also utilizes unique developmental mechanisms that may be sensitive to perturbation in disease pathogenesis. Indeed, abnormalities of postnatal hippocampal development have been implicated in the pathophysiology of depression, schizophrenia, epilepsy, and addiction. This project will particularly focus on the role of transcription factors, especially Tbr2, in postnatal hippocampal development. Preliminary studies for this project demonstrate that Tbr2 is essential for development of the dentate gyrus: conditional Tbr2 inactivation causes severe hypoplasia of the dentate gyrus, with defects of cell migration and differentiation. To further investigate the mechanisms affected, we will pursue the following 2 specific aims: (1) First, we will analyze and compare the migrations of different progenitor cell types and neurons in normal and Tbr2 conditional null postnatal hippocampus using a battery of cell type specific markers. (2) Second, we will use multiphoton time-lapse imaging to directly observe and characterize the migrations of different progenitor types in normal and Tbr2 conditional null postnatal hippocampus. Upon completion of these studies, we will have defined mechanisms of cell migration in the postnatal dentate gyrus and their regulation by transcription factor Tbr2. These insights will provide a more detailed scientific basis for understanding diseases involving abnormal hippocampal development. This project fulfills Recovery Act goals by accelerating the tempo of progress in this research area, and by providing for the retention and employment of scientists, through increased effort as well as creation of a new job position for a research technician. PUBLIC HEALTH RELEVANCE: Abnormalities of neurogenesis in the postnatal and adult dentate gyrus (DG) of the hippocampus have been implicated in the pathophysiology of several neuropsychiatric diseases, including depression, schizophrenia, epilepsy, and addiction. This revision project extends our analysis of adult neurogenesis in the DG, to further investigate basic mechanisms of dentate gyrus development in the postnatal period. In particular, defects of cell migration, differentiation, and hippocampal morphogenesis will be studied in targeted genetic mutant mice deficient in the transcription factor Tbr2. These studies will not only improve our understanding of disease mechanisms but also enhance approaches to neuroregeneration as a potential therapeutic approach.

描述（由申请人提供）：该项目修订将我们对海马神经发生的分析从成年期（父母资助的重点）扩展到小鼠的出生后年龄。母项目的总体目标是更好地了解成人海马神经发生、其机制和调节。成人神经发生对于设计神经替代疗法策略具有重要意义，神经替代疗法可用于治疗神经退行性疾病和其他神经元损失病症。该修订项目的目标是深入了解海马体的出生后发育，特别是齿状回。齿状回的发育不仅为成人神经发生奠定了基础，而且利用了可能对疾病发病机制中的扰动敏感的独特发育机制。事实上，出生后海马发育异常与抑郁症、精神分裂症、癫痫和成瘾的病理生理学有关。该项目将特别关注转录因子（尤其是 Tbr2）在产后海马发育中的作用。该项目的初步研究表明，Tbr2对于齿状回的发育至关重要：条件性Tbr2失活会导致齿状回严重发育不全，导致细胞迁移和分化缺陷。为了进一步研究受影响的机制，我们将追求以下 2 个具体目标：（1）首先，我们将使用一组细胞类型特异性标记物分析和比较正常和 Tbr2 条件无效出生后海马中不同祖细胞类型和神经元的迁移。 (2)其次，我们将使用多光子延时成像直接观察和表征正常和Tbr2条件无效出生后海马中不同祖细胞类型的迁移。完成这些研究后，我们将确定出生后齿状回细胞迁移的机制及其转录因子 Tbr2 的调节。这些见解将为理解涉及海马发育异常的疾病提供更详细的科学依据。该项目通过加快该研究领域的进展速度、通过加大努力以及为研究技术人员创造新的工作职位来留住和雇用科学家来实现《复苏法案》的目标。 公共卫生相关性：出生后和成人海马齿状回 (DG) 的神经发生异常与多种神经精神疾病的病理生理学有关，包括抑郁症、精神分裂症、癫痫和成瘾。该修订项目扩展了我们对 DG 中成人神经发生的分析，以进一步研究出生后齿状回发育的基本机制。特别是，将在缺乏转录因子 Tbr2 的靶向基因突变小鼠中研究细胞迁移、分化和海马形态发生的缺陷。这些研究不仅将提高我们对疾病机制的理解，还将增强神经再生作为潜在治疗方法的方法。