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

• 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
• 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

 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）：建立细胞命运和突触可塑性的转录途径我们假设FOXO转录因子在果蝇的整个生命周期中控制运动神经元的可塑性。FOXO是进化上保守的蛋白质，协调细胞对发育和环境刺激的反应。众所周知，它们在调节健康衰老和应激反应的分子回路中的中心地位，它们的发育功能最近成为焦点。特别是，FOXO已经成为大脑发育的重要调节器。FOXO的神经元功能已经在小鼠、C.线虫和果蝇。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。虽然FOXO蛋白是神经元发育和生理学多个方面的关键调节因子，但它们作用的神经元特异性途径尚未确定。在这里，我们提出了一种新的神经元FOXO通路的分析组件，结合分子，遗传和全基因组的方法。我们将测试的假设，FOXO活性刺激Toll-6信号，以抑制胚胎发生过程中的细胞凋亡，促进突触组织和可塑性在幼虫发育。对FOXO在这些过程中的作用的机制性理解需要鉴定其转录靶点。为此，我们提出了一种无偏的大规模RNA-seq方法来识别FOXO依赖的转录组。因此，我们提出了一个全新的途径，以及效应分子的全基因组筛选的初步表征。总之，这些研究的目的是在一个强大的遗传模型系统中定义一种新的从细胞表面到核反应的神经营养途径。在神经退行性疾病、正常衰老和损伤等不同背景下，调节神经营养通路的存活和突触功能具有重要意义。建议的全基因组效应筛选可能会在这些关键信号通路中提出意想不到的和新的参与者。