Developmental regulation of neural stem cell elimination

神经干细胞消除的发育调节

• 批准号: 8190028
• 负责人: Sarah Elizabeth Siegrist
• 金额: $ 9.54万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190028
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adult; Age-associated memory impairment; Anencephaly; Apoptosis; Autophagocytosis; Back; Biological; Biological Models; Biological Process; Brain; Brain Neoplasms; Cancer Biology; Cell Count; Cell Cycle; Cell Death; Cell Survival; Cell division; Cells; Cessation of life; Complex; Cues; Cytokine Signaling; Defect; Development; Disease; Down-Regulation; Drosophila genus; Ensure; Foundations; Genes; Genetic; Genetic Screening; Goals; Growth; Human; Individual; Injury; Insulin; Knowledge; Learning; Mammals; Mediating; Membrane; Memory; Mentorship; Methods; Microcephaly; Molecular; Mood Disorders; Mushroom Bodies; Nervous system structure; Neuroglia; Neurons; Nuclear; Organism; Pathway interactions; Pattern; Physiological; Play; Population; Positioning Attribute; Radial; Regulation; Research; Research Proposals; Research Training; Role; Signal Transduction; Somatic Cell; Stem cell transplant; Stem cells; Synapses; Testing; Testis; Therapeutic; Time; Tissues; Work; base; brain cell; brain size; cell growth; cell type; fascinate; fly; gene function; human disease; improved; inhibition of autophagy; insight; meetings; nerve stem cell; neuroblast; neurogenesis; novel; postnatal; prevent; progenitor; regenerative; relating to nervous system; self-renewal; stem; stem cell biology; stem cell division; tool; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): The sheer number and diversity of cell types within the human brain is staggering. Understanding how this cell diversity is generated and organized in such a way that allows organisms to think and behave is of fundamental importance. All neurons within the brain are generated from neural stem cells, which are self-renewing multi-potent progenitors. Neural stem cells play a key role in regulating brain size and cell type diversity, since this population remains actively engaged in the cell cycle throughout development. While much effort is aimed towards identifying the molecular mechanisms regulating stem cell self-renewal, I have become fascinated by the converse. What are the molecular mechanisms that terminate neural stem cell divisions once development is complete, which is essential to ensure proper formation of brain circuitry and to inhibit tissue overgrowth and tumorigenesis. Beyond development, the answer to this question is of key importance for under-standing age- related cognitive declines, mood disorders, and limited regenerative capacity of adult brains. Here we use Drosophila as a model system in which to investigate the mechanisms that terminate the cell divisions of neural stem cells, known as neuroblasts in Drosophila. We find that a subset of neuroblasts, are eliminated during development by cell death. If death fails, then neuroblasts persist long term in the adult brain and continue generating new neurons. Flies provide an excellent model system for studying the mechanisms regulating neural stem cell elimination, because the brain is vastly less complex than mammals, there exists a range of sophisticated genetic tools for manipulating gene function, and many biological processes are evolutionarily conserved. The goal of this proposal is to identify extrinsic and intrinsic cues that regulate neural stem cell elimination using a genetic and cell biological approach. The first aim tests the hypothesis that ensheathing glia provide trophic support necessary for neuroblast survival. The second aim investigates whether neuroblasts enter autophagy, prior to their elimination via cell death, which may serve as a potent backup mechanism to ensure termination of neuroblast proliferation. In addition, we will carry out an unbiased forward genetic screen to identify genes required for neuroblast elimination. Finally, we propose to transition our work to a mammalian model system, which will provide greater insight into understanding human disease. One more long-term goal is to use Drosophila as a means for identifying genes required for neural stem cell elimination, and then test whether the mammalian orthologues share this common function. Under the mentorship of Dr. Iswar Hariharan, an expert in genetics and cancer biology, and under the guidance of Dr. Arturo Alvarez-Buylla, Dr. David Schaffer, and Dr. Andy Wurmser, all experts in mammalian neural stem cells and neurogenesis, the candidate will gain expertise in genetic screening, using mammalian model systems, and mammalian neural stem cell biology. This research and training plan will provide her with an excellent foundation with which to transition to an independent research position. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify the molecular mechanisms that terminate cell divisions of neural stems during development. The results from the proposed research could provide insight into: 1) improving stem cell therapeutics by devising methods to promote stem cell survival. 2) determining whether aberrantly persisting neural stem cells cause brain tumors. 3) devising methods to replace neurons damaged by disease or injury. 4) a greater understanding of the basis of congenital brain defects, such as anencephaly or microcephaly.

描述（由申请人提供）：人脑内细胞类型的庞大数量和多样性令人惊叹。了解这种细胞多样性是如何产生和组织的，以使生物可以思考和行为的方式至关重要。大脑内的所有神经元都是由神经干细胞产生的，这些神经干细胞是自我更新的多力量祖细胞。神经干细胞在调节脑大小和细胞类型多样性方面起着关键作用，因为该人群在整个发育过程中仍在积极参与细胞周期。尽管旨在确定调节干细胞自我更新的分子机制的努力，但我已经对匡威着迷。一旦完整发育，终止神经干细胞分裂的分子机制是什么，这对于确保正确形成脑电路并抑制组织过度生长和肿瘤发生至关重要。除了发展之外，这个问题的答案对于成年人大脑的不足年龄相关的认知能力，情绪障碍和有限的再生能力至关重要。 在这里，我们使用果蝇作为模型系统，在其中研究终止神经干细胞细胞分裂的机制，即果蝇中称为神经细胞。我们发现，通过细胞死亡在发育过程中消除了神经细胞的子集。如果死亡失败，那么成人大脑的神经细胞长期持续存在，并继续产生新的神经元。苍蝇为研究调节神经干细胞消除的机制提供了出色的模型系统，因为大脑比哺乳动物复杂得多，因此存在一系列用于操纵基因功能的复杂遗传工具，并且许多生物学过程在进化上是保守的。该提案的目的是确定使用遗传和细胞生物学方法来调节神经干细胞消除神经干细胞的外在和内在提示。第一个目的检验了一个假设，即开发胶质可提供神经细胞存活所需的营养支持。第二个目标研究神经细胞是否在通过细胞死亡消除之前进入自噬，这可能是确保终止神经细胞增殖的有效备份机制。此外，我们将执行一个公正的前向遗传筛选，以识别消除神经细胞所需的基因。最后，我们建议将工作过渡到哺乳动物模型系统，该系统将为理解人类疾病提供更多的了解。一个更长期的目标是将果蝇作为识别消除神经干细胞所需的基因的手段，然后测试哺乳动物直系同源物是否具有这种共同的功能。 在遗传学和癌症生物学专家Iswar Hariharan博士的指导下，在Arturo Alvarez-Buylla博士，David Schaffer博士和Andy Wurmser博士的指导下，所有哺乳动物神经干细胞的专家和神经神经发生的专家都将使用遗传筛查型神经模型，并在MAMMAMAL模型模型中获得专业知识。该研究和培训计划将为她提供出色的基础，以过渡到独立的研究职位。 公共卫生相关性：该项目的目的是确定在发育过程中终止神经茎细胞分裂的分子机制。拟议研究的结果可以提供：1）通过设计方法来促进干细胞存活方法来改善干细胞疗法。 2）确定异常持续存在神经干细胞是否引起脑肿瘤。 3）设计方法来替代因疾病或损伤损害的神经元的方法。 4）对先天性大脑缺陷的基础，例如肌畸形或小头畸形。