Establishing a transcriptional pathway for cell-fate and synaptic plasticity

建立细胞命运和突触可塑性的转录途径

基本信息

批准号：
8815445
负责人：
Heather Broihier
金额：
$ 19.81万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8815445
关键词：
Apoptosis Biological Models Brain Caenorhabditis elegans Cell Death Cell Survival Cell surface Cells Characteristics Development Drosophila genus Embryo Embryonic Development Environment Funding Mechanisms Gene Expression Profile Genes Genetic Models Injury Ion Channel Life Light Longevity Memory Modeling Molecular Molecular Genetics Morphology Motor Neurons Mus Neurodegenerative Disorders Neurons Neurotransmitters Nuclear Pathway interactions Physiology Population Positioning Attribute Process Proteins Regulation Role Shapes Signal Pathway Signal Transduction Specificity Staging Stimulus Synapses Synaptic plasticity Testing Work base biological adaptation to stress cell type extracellular flexibility gain of function genome wide association study genome-wide healthy aging interest mutant neuron development normal aging novel presynaptic programs public health relevance receptor research study response synaptic function transcription factor transcriptome sequencing

Apoptosis Biological Models Brain Caenorhabditis elegans Cell Death Cell Survival Cell surface Cells Characteristics Development Drosophila genus Embryo Embryonic Development Environment Funding Mechanisms Gene Expression Profile Genes Genetic Models Injury Ion Channel Life Light Longevity Memory Modeling Molecular Molecular Genetics Morphology Motor Neurons Mus Neurodegenerative Disorders Neurons Neurotransmitters Nuclear Pathway interactions Physiology Population Positioning Attribute Process Proteins Regulation Role Shapes Signal Pathway Signal Transduction Specificity Staging Stimulus Synapses Synaptic plasticity Testing Work base biological adaptation to stress cell type extracellular flexibility gain of function genome wide association study genome-wide healthy aging interest mutant neuron development normal aging novel presynaptic programs public health relevance receptor research study response synaptic function transcription factor transcriptome sequencing

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项目摘要

DESCRIPTION (provided by applicant): Establishing a transcriptional pathway for cell-fate and synaptic plasticity We hypothesize that the FOXO transcription factor controls motoneuron plasticity across lifespan in Drosophila. FOXOs are evolutionarily conserved proteins that coordinate cellular responses to developmental and environmental stimuli. Well known for their central position in molecular circuits regulating healthy aging and stress responses, their developmental functions have recently come into focus. In particular, FOXOs have emerged as important regulators of brain development. Neuronal functions of FOXOs have been investigated in mice, C. elegans, and Drosophila. To date, these functions include neuronal polarity, morphology, synaptic function, and memory consolidation. Though FOXO proteins are key regulators of multiple aspects of neuronal development and physiology, the neuronal-specific pathways in which they act are as yet undefined. Here we propose to analyze components of a novel neuronal FOXO pathway using combined molecular, genetic, and genome-wide approaches. We will test the hypothesis that FOXO activity is stimulated by Toll-6 signaling to inhibit apoptosis during embryogenesis and promote synaptic organization and plasticity during larval development. Mechanistic under- standing of FOXO's role in these processes requires the identification of its transcriptional targets. To this end, we propose an unbiased large-scale RNA-seq approach to identify the FOXO-dependent transcriptome. Thus, we propose an initial characterization of an entirely novel pathway, as well as a genome-wide screen for effector molecules. Together, these studies aim to define a novel neurotrophic pathway from cell surface to nuclear response in a powerful genetic model system. There is significant interest in modulating both the survival and synaptic functions of neurotrophic pathways in contexts as varied as neurodegenerative diseases, normal aging, and injury. The proposed genome- wide screens for effectors may suggest unexpected and novel players in these critical signaling pathways.

描述（由适用提供）：建立用于细胞污染和突触可塑性的转录途径，我们假设FOXO转录因子控制果蝇中整个生命周期的运动神经元可塑性。 FOXOS是进化配置的蛋白质，可协调对发育和环境刺激的细胞反应。他们的发育功能以调节健康衰老和压力反应的分子回路中的中心位置而闻名，最近开始焦点。特别是，Foxos已成为大脑发育的重要调节因子。在小鼠，秀丽隐杆线虫和果蝇中已经研究了FoxOS的神经元功能。迄今为止，这些功能包括神经元极性，形态，突触功能和记忆巩固。尽管FOXO蛋白是神经元发育和生理学多个方面的关键调节剂，但它们尚未定义的神经元特异性途径。在这里，我们建议使用分子，遗传和全基因组方法的组合分析新型神经元FOXO途径的组件。我们将检验以下假设：FOXO活性是通过TOLL-6信号传导刺激的，以抑制胚胎发生过程中的凋亡，并促进幼虫发育过程中的突触组织和可塑性。 FOXO在这些过程中的作用的理解要求识别其转录靶标。为此，我们提出了一种公正的大规模RNA-seq方法来识别依赖FoxO的转录组。这，我们提出了完全新颖的途径的初始表征，以及效应分子的全基因组筛选。这些研究旨在在强大的遗传模型系统中定义从细胞表面到核反应的新型神经营养途径。在调节神经营养疾病，正常衰老和损伤的情况下，神经营养途径的生存和突触功能具有重大兴趣。提出的效果基因组范围可能表明这些关键信号通路中的意外和新颖的参与者。