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

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（由申请人提供）：可估算的细胞效果和突触塑料塑料的转录途径我们假设果蝇的生命周期中的分子控制因素是进化的蛋白质。尤其是福克斯（Foxos）的重点。生理学d。我们提出，使用分子，遗传和全基因组的组合分析NO uronal foxo的成分幼虫的速度在强大的遗传模型系统中，从塞尔法斯到核反应。在这些关键的信号通路中出乎意料且新颖的参与者。