Genetic and Molecular Studies of Neurogenesis

神经发生的遗传和分子研究

基本信息

批准号：
8446285
负责人：
Chris Q Doe
金额：
$ 27.35万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-09-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8446285
关键词：
Age Amacrine Cells Animal Model Behavior Biological Models Brain Brain Diseases Cells Competence Complex Cues Data Defect Development Disease Drosophila genus Embryo Embryonic Development Epigenetic Process Erinaceidae Funding Generations Genes Genetic Health Benefit Human Knowledge Life Lobe Mammals Mental disorders Methods Mission Mitotic Molecular Genetics Nervous system structure Neuraxis Neurons Nuclear Protein Nuclear Proteins Organism Orthologous Gene Pathway interactions Patients Pattern Physiologic pulse Positioning Attribute Primates Process Production Prosencephalon Proteins Public Health Recruitment Activity Research Retinal Retinal Ganglion Cells Role Series Societies Somatic Cell Specific qualifier value Spinal Cord Stem cells Stroke Structure Testing Therapeutic Time Tissues To specify Traumatic Brain Injury United States National Institutes of Health Ventricular Vision Work age related cell type design fly follow-up ganglion cell hindbrain induced pluripotent stem cell insight nerve stem cell nervous system disorder neuroblast neurogenesis notch protein progenitor regenerative therapy relating to nervous system response retinal neuron stem stem cell differentiation stem cell therapy tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): We are investigating how the central nervous system (CNS) is assembled during embryonic development. This is has several potential human health benefits relevant to the NIH mission. First, the treatment of many neurological disorders would benefit from a method for generating specific types of neurons from the patient's own induced pluripotent stem (IPS) cells. Second, many psychiatric disorders arise in part from developmental defects. Generating therapeutic tools to treat these types of disorders will require a detailed understanding of how each neuronal subtype is normally formed. We have been investigating this question in the model organism Drosophila, which has been profoundly important for discovering mechanisms of neurogenesis relevant in mammals. Much is currently known about how neural progenitors acquire their spatial identity (e.g. forebrain vs. hindbrain) but we still know very little about how they sequentially produce different cell types. We previously identified a series of transcription factors that specify temporal identity within the Drosophila nervous system. Here we focus on three related questions in embryonic progenitors (Aims 1-3) and conclude with the first analysis of temporal identity in a newly discovered Drosophila post- embryonic neural progenitor that shares features with the primate outer ventricular zone progenitor (Aim 4). In Aim 1, we will determine whether the Hunchback transcription factor acts transiently in progenitors or continuously in post-mitotic neurons to specify "first-born" temporal identity. Because the mammalian Hunchback ortholog Ikaros has a similar role in specifying early-born retinal ganglion cell fates, this aim has the potential to hep design therapeutic treatments to replace a cell type essential for human vision. In Aim 2, we follow up on results from the previous funding period showing that neural progenitors lose competence over time to form early-born neuron subtypes in response to a pulse of Hunchback expression. We will determine the mechanism of "progressive loss of competence" in these progenitors, aided by the identification of a nuclear protein whose expression mimics the competence window, and whose prolonged expression can extend the competence window. In Aim 3, we initiate work on a new "Type II" neural stem cell that we and others recently discovered. Each brain lobe contains 8 type II neuroblasts that divide asymmetrically to produce a series of "intermediate neural progenitors (INPs) that each also divide asymmetrically to make a sequence of 10-12 neurons. We will characterize the relationship between neuroblast or INP birthorder and the production of distinct neural subtypes. We have recently identified transcription factors expressed in sequentially in INPs, and we will determine if they specify temporal identity in these sublineages.

描述（由申请人提供）：我们正在研究如何在胚胎发育过程中组装中枢神经系统（CNS）。这是与NIH任务相关的几种潜在人类健康益处。首先，对许多神经系统疾病的治疗将受益于一种从患者自身诱导的多能茎（IPS）细胞中产生特定类型神经元的方法。其次，许多精神疾病部分来自发育缺陷。生成治疗这些类型疾病的治疗工具将需要详细了解通常如何形成每个神经元亚型。我们一直在研究果蝇模型中研究这个问题，这对于发现在哺乳动物中相关的神经发生机制非常重要。目前，关于神经祖细胞如何获得其空间身份（例如前脑和后脑）的知识已有很多知识，但我们仍然对它们如何依次产生不同的细胞类型的了解知之甚少。我们先前确定了一系列指定果蝇神经系统中时间身份的转录因子。在这里，我们关注胚胎祖细胞中的三个相关问题（AIMS 1-3），并在新发现的果蝇后胚胎神经祖细胞中首次分析时间身份，该问题与灵长类动物外心室区域祖细胞共享特征（AIM 4）。在AIM 1中，我们将确定驼背转录因子是在祖细胞中瞬时起作用还是在有丝分裂后神经元中连续起作用，以指定“长生”的时间身份。由于哺乳动物的驼背直角Ikaros在指定早期出生的视网膜神经节细胞命运方面具有相似的作用，因此该目标有可能HEP设计治疗方法来替代对人类视力必不可少的细胞类型。在AIM 2中，我们跟进了上一个融资期的结果，表明神经祖细胞随着时间的流逝而失去能力，以响应驼背表达的脉搏而形成早期出生的神经元亚型。我们将在这些祖细胞中“逐渐丧失能力丧失”的机制，在识别核蛋白的识别的帮助下，其表达模仿了能力窗口，并且其延长表达可以扩展能力窗口。在AIM 3中，我们启动了我们和其他最近发现的新“ II”神经干细胞的工作。 Each brain lobe contains 8 type II neuroblasts that divide asymmetrically to produce a series of "intermediate neural progenitors (INPs) that each also divide asymmetrically to make a sequence of 10-12 neurons. We will characterize the relationship between neuroblast or INP birthorder and the production of distinct neural subtypes. We have recently identified transcription factors expressed in sequentially in INPs, and we will determine if they在这些sublineage中指定时间身份。