Mechanisms of the programmed cell death of post-embryonic neurons

胚胎后神经元程序性细胞死亡的机制

• 批准号: 9284129
• 负责人: JAE H PARK
• 金额: $ 6.2万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9284129
• 关键词: Adolescent; Adult; Alzheimer' s Disease; Amphibia; Animals; Apoptosis; Apoptotic; Architecture; Biological; Biological Metamorphosis; Biological Models; CRISPR/Cas technology; Caspase; Cell Death; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Drosophila genome; Drosophila genus; Ecdysone; Embryo; Embryonic Development; Event; Fetal Development; Gene Expression; Genes; Genetic; Genetic Models; Genome engineering; Goals; Health; Insecta; Invertebrates; Knock-in; Lead; Luciferases; Malignant - descriptor; Mammals; Maps; Modeling; Modification; Molecular; Nerve; Neuraxis; Neurodegenerative Disorders; Neurons; Open Reading Frames; Organ; Paper; Parkinson Disease; Pattern; Phenotype; Play; Puberty; Publishing; Regulation; Reporter Genes; Research; Role; Sculpture; Signal Transduction; Teenagers; Time; Tissues; Training; Ursidae Family; Vertebrates; Work; bursicon; critical developmental period; fly; graduate student; in vivo; insight; nervous system development; neural circuit; neurochemistry; neuron apoptosis; neuron loss; novel; programs; relating to nervous system; sensor; tool; undergraduate student

 DESCRIPTION (provided by applicant): Programmed cell death (PCD) of neurons is very important developmental event to establish functional central nervous system (CNS) via eliminating obsolete neurons. During metamorphic development, certain larval neurons selectively undergo PCD in both vertebrates and invertebrates. Thus, disruption of such developmentally controlled neuronal PCD results in the aberrant formation of adult CNS. Puberty in mammals is comparable to metamorphosis in amphibians and insects, and extensive neuronal modifications in the CNS take place during this period as well. Such a transitional CNS is a causative reason why teens are emotionally and psychologically unstable. However, it is not well understood what types of juvenile neurons are selectively fated to die, and how such selection is made. Drosophila is an excellent model system to tackle these questions, as sophisticated neuro-genetic tools are available. To understand the significance and mechanisms of neuronal PCD during fly metamorphosis, we propose two specific aims in this proposal: (1) we will establish the first comprehensive neuroanatomical map of dying neurons by identifying their neurochemical phenotypes. Since functions of differentiated neurons are dictated by the neurochemical transmitters they bear, this aim will determine which types (functions) of juvenile neurons are programmed to die. Except for 28 larval neurons, we do not know the neurochemical identities of other ~300 doomed neurons. For this aim, we will develop a new in vivo cell death marker to conveniently detect dying neurons. Identification of dying neurons will be done by using specific gal4 drivers. (2) We propose to determine to what extent grim, a critical apoptotic gene in Drosophila CNS, plays a role in the neuronal PCD and to understand how grim expression is regulated. We will employ a novel genome engineering tool, CRISPR, to generate knock-in of grim with reporter genes. These studies will allow us to understand how apoptotic gene expression is induced during metamorphosis. Throughout these works, we expect to train both undergraduate and graduate students and to publish one research paper from each specific aim. Our proposed studies in Drosophila will provide an insight into the role of neuronal PCD during puberty in mammals.

 描述（由申请人提供）：神经元的程序性细胞死亡（PCD）是通过消除废弃神经元建立功能性中枢神经系统（CNS）的非常重要的发育事件。在变态发育过程中，脊椎动物和无脊椎动物的某些幼虫神经元选择性地经历 PCD。因此，这种发育控制神经元 PCD 的破坏会导致成人 CNS 的异常形成。哺乳动物的青春期类似于两栖动物和昆虫的变态，中枢神经系统中的广泛神经元也在这个时期发生变化。这种过渡性中枢神经系统是青少年情绪和心理不稳定的原因之一。然而，目前尚不清楚哪些类型的幼年神经元会选择性地死亡，以及这种选择是如何进行的。果蝇是解决这些问题的优秀模型系统，因为可以使用复杂的神经遗传学工具。为了了解果蝇变态过程中神经元PCD的重要性和机制，我们在该提案中提出了两个具体目标：（1）我们将通过识别垂死神经元的神经化学表型来建立第一个全面的垂死神经元的神经解剖图。由于分化神经元的功能是由它们所携带的神经化学递质决定的，因此这一目标将决定哪些类型（功能）的幼年神经元被编程死亡。除了 28 个幼虫神经元之外，我们不知道其他约 300 个注定失败的神经元的神经化学特性。为此，我们将开发一种新的体内细胞死亡标记物，以方便地检测垂死的神经元。垂死神经元的识别将通过使用特定的 gal4 驱动程序来完成。 (2) 我们建议确定果蝇 CNS 中的关键凋亡基因 grim 在神经元 PCD 中发挥作用的程度，并了解 grim 表达是如何受到调节的。我们将采用一种新型基因组工程工具 CRISPR，用报告基因敲入 grim。这些研究将使我们了解变态过程中如何诱导凋亡基因表达。在这些工作中，我们希望培训本科生和研究生，并针对每个特定目标发表一篇研究论文。我们提出的果蝇研究将深入了解哺乳动物青春期期间神经元 PCD 的作用。

项目成果

Simulation of Preterm Neonatal Brain Metabolism During Functional Neuronal Activation Using a Computational Model.

• DOI: 10.1007/978-1-4939-3023-4_14
• 发表时间: 2016
• 期刊: Advances in experimental medicine and biology
• 作者: Hapuarachchi T;Scholkmann F;Caldwell M;Hagmann C;Kleiser S;Metz AJ;Pastewski M;Wolf M;Tachtsidis I
• 通讯作者: Tachtsidis I

Cloning and functional characterizations of an apoptogenic Hid gene in the Scuttle Fly, Megaselia scalaris (Diptera; Phoridae).

Scuttle Fly, Megaselia scalaris（双翅目； Phoridae）中凋亡 Hid 基因的克隆和功能特征。

• DOI: 10.1016/j.gene.2016.11.043
• 发表时间: 2017
• 期刊: Gene
• 影响因子: 3.5
• 作者: Yoo,Siuk;Lam,Haylie;Lee,Chansong;Lee,Gyunghee;Park,JaeH
• 通讯作者: Park,JaeH