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）：人脑内细胞类型的绝对数量和多样性是惊人的。了解这种细胞多样性是如何产生和组织的，从而使生物体能够思考和行为，这一点至关重要。大脑内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能祖细胞。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，因为该群体在整个发育过程中仍然积极参与细胞周期。尽管人们付出了很多努力来确定调节干细胞自我更新的分子机制，但我却对相反的情况着迷。一旦发育完成，终止神经干细胞分裂的分子机制是什么，这对于确保大脑回路的正确形成并抑制组织过度生长和肿瘤发生至关重要。除了发育之外，这个问题的答案对于理解与年龄相关的认知衰退、情绪障碍和成人大脑再生能力有限也至关重要。 在这里，我们使用果蝇作为模型系统，研究终止神经干细胞（果蝇中称为神经母细胞）的细胞分裂的机制。我们发现神经母细胞的一个子集在发育过程中通过细胞死亡而被消除。如果死亡失败，那么成神经细胞会长期存在于成人大脑中并继续产生新的神经元。果蝇为研究调节神经干细胞消除的机制提供了一个极好的模型系统，因为大脑比哺乳动物简单得多，存在一系列复杂的遗传工具来操纵基因功能，并且许多生物过程在进化上是保守的。该提案的目标是使用遗传和细胞生物学方法来识别调节神经干细胞消除的外在和内在线索。第一个目标检验这样的假设：鞘状神经胶质细胞为神经母细胞的生存提供必要的营养支持。第二个目标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，这可能作为确保神经母细胞增殖终止的有效后备机制。此外，我们将进行无偏见的正向遗传筛选，以确定消除神经母细胞所需的基因。最后，我们建议将我们的工作转移到哺乳动物模型系统，这将为理解人类疾病提供更深入的见解。另一个长期目标是利用果蝇作为识别神经干细胞消除所需基因的手段，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查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职位提供良好的基础。 公共健康相关性：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。拟议研究的结果可以提供以下方面的见解：1）通过设计促进干细胞存活的方法来改进干细胞治疗。 2）确定异常持续存在的神经干细胞是否会导致脑肿瘤。 3）设计方法来替代因疾病或损伤而受损的神经元。 4）更好地了解先天性脑缺陷的基础，例如无脑畸形或小头畸形。