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)：人脑中细胞类型的绝对数量和多样性令人震惊。了解这种细胞多样性是如何产生和组织的，从而使有机体能够思考和行为，这一点至关重要。大脑中的所有神经元都是由神经干细胞产生的，神经干细胞是自我更新的多潜能前体细胞。神经干细胞在调节大脑大小和细胞类型多样性方面发挥着关键作用，因为这一群体在整个发育过程中仍积极参与细胞周期。虽然很多努力都是为了识别调控干细胞自我更新的分子机制，但我对相反的情况很感兴趣。一旦发育完成，终止神经干细胞分裂的分子机制是什么，这对于确保大脑电路的正确形成以及抑制组织过度生长和肿瘤发生至关重要。除了发育，这个问题的答案对于了解与年龄相关的认知下降、情绪障碍和成人大脑有限的再生能力具有关键重要性。在这里，我们使用果蝇作为一个模型系统，在其中研究终止神经干细胞的细胞分裂的机制，即果蝇中的神经母细胞。我们发现，神经母细胞的一个子集，在发育过程中被细胞死亡消除。如果死亡失败，神经母细胞就会在成人大脑中长期存在，并继续生成新的神经元。苍蝇为研究神经干细胞消除的调控机制提供了一个很好的模型系统，因为大脑远没有哺乳动物复杂，存在一系列复杂的遗传工具来操纵基因功能，而且许多生物过程在进化上是保守的。这项建议的目标是确定使用遗传和细胞生物学方法来调控神经干细胞消除的外在和内在线索。第一个目的是验证这样的假设，即成鞘的神经胶质细胞为神经母细胞的生存提供必要的营养支持。第二个目的是研究神经母细胞在通过细胞死亡消除之前是否进入自噬，这可能是确保终止神经母细胞增殖的一种有效的后备机制。此外，我们将进行无偏见的正向基因筛查，以确定神经母细胞消除所需的基因。最后，我们建议将我们的工作过渡到哺乳动物模型系统，这将为理解人类疾病提供更好的见解。另一个长期目标是利用果蝇作为一种手段来识别消除神经干细胞所需的基因，然后测试哺乳动物的同源基因是否具有这一共同功能。在遗传学和癌症生物学专家Iswar Hariharan博士的指导下，在哺乳动物神经干细胞和神经发生方面的专家Arturo Alvarez-Buylla博士、David Schaffer博士和Andy Wurmser博士的指导下，候选人将获得使用哺乳动物模型系统进行基因筛选和哺乳动物神经干细胞生物学方面的专业知识。这项研究和培训计划将为她过渡到独立研究岗位提供良好的基础。 公共卫生相关性：该项目的目标是确定在发育过程中终止神经干细胞分裂的分子机制。这项拟议研究的结果可能为以下方面提供洞察力：1)通过设计促进干细胞存活的方法来改进干细胞疗法。2)确定异常存活的神经干细胞是否会导致脑瘤。3)设计替换因疾病或损伤而受损的神经元的方法。4)更好地了解先天性脑缺陷的基础，如无脑儿或小头畸形。