Mechanisms of sensory neuron morphological diversification, signaling, and functional plasticity

感觉神经元形态多样化、信号传导和功能可塑性的机制

• 批准号: 9274742
• 负责人: Piali Sengupta
• 金额: $ 59.37万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274742
• 关键词: Address; Afferent Neurons; Anatomy; Animals; Architecture; Area; Award; Behavior; Behavioral; Caenorhabditis elegans; Cellular biology; Cilia; Cues; Defect; Development; Disease; Environment; Exhibits; Funding; Genetic; Genetic Transcription; Goals; Human; Individual; Investigation; Lead; Mammalian Cell; Mammals; Modality; Molecular; Morphology; National Institute of General Medical Sciences; Nematoda; Nervous system structure; Neuronal Plasticity; Neurons; Organelles; Organism; Pathology; Pathway interactions; Property; Proteins; Research; Research Training; Sensory; Shapes; Signal Transduction; Signaling Molecule; Stimulus; Structure; Temperature; Therapeutic; Work; behavioral response; cell type; experience; functional plasticity; innovation; insight; nervous system disorder; neuron development; neuronal circuitry; neurotransmission; novel; response; sensory mechanism

PROJECT SUMMARY The overall goal of NIGMS-funded research in my lab is to describe the molecular and cellular mechanisms by which individual sensory neuron types acquire their distinctive morphologies and functions, and explore how these properties are further shaped by the animal's experience and environment. In one area, we investigate how sensory neurons in C. elegans elaborate cell type-specific cilia, organelles that house sensory signaling molecules. In a second area, we characterize the mechanisms by which C. elegans exhibits highly sensitive and experience-dependent responses to environmental temperature, a critical but poorly understood sensory modality. These issues are interdependent; neuronal anatomy governs neuronal function, and conversely, neuronal activity shapes neuronal morphology. Integrating these projects will not only allow us to continue our ongoing successful research strategies, but will also enable us to initiate novel avenues of investigation. A first major goal for the next several years is to develop a detailed understanding of the genetic pathways by which ciliary morphological diversity is achieved. Structurally unique cilia are critical for the functions of specific sensory neuron types in multiple species. Although ciliogenic mechanisms are now well-described, how diversity in ciliary structures is generated is unclear. We plan to analyze mechanisms generating ciliary morphological diversity in C. elegans, and also expand our analysis to mammalian cells. A second major goal is to dissect the properties of a class of novel but conserved thermosensory molecules that we recently described, and to explore how these proteins contribute to the extraordinary experience-dependent thermosensitivity of a sensory neuron type. We will also examine how transcriptional and translational changes in single thermosensory neuron types contribute to state- and experience-dependent plasticity in neuronal and circuit properties to alter thermosensory behaviors. A particularly innovative goal is to combine our expertise in neuronal cell biology and analysis of stimulus-evoked sensory responses to systematically describe how sensory activity modulates cilia protein composition and neuronal function, and conversely, explore how cilia architecture dictates sensory neuron response profiles. Under this combined award, we will be able to employ our multifaceted experimental approach to broaden and deepen our analysis of neuronal form and function, incorporate conceptual and experimental innovations to establish new research directions, and provide a more integrative research training experience. Defects in cilia structure and function, as well as altered neuronal signaling and plasticity, underlie a plethora of neurological disorders. Given the extensive conservation of ciliogenic as well as neuronal pathways between mammals and C. elegans, we fully expect that findings from this work will influence and guide related investigations in other organisms in both development and disease.

项目摘要 在我的实验室中，由NIGMS资助的研究的总体目标是通过描述分子和细胞机制 哪种个人感觉神经元类型获得了其独特的形态和功能，并探讨了如何 这些特性是由动物的经验和环境进一步塑造的。在一个地区，我们调查 秀丽隐杆线虫中的感官神经元如何精心构造的细胞类型特异性纤毛，嵌入感官信号的细胞器 分子。在第二个区域，我们表征了秀丽隐杆线虫表现高度敏感的机制 以及对环境温度的依赖经验的反应，这是一种关键但知之甚少的感觉 方式。这些问题是相互依存的。神经元解剖控制神经元功能，相反， 神经元活性塑造神经元形态。整合这些项目不仅可以使我们继续我们的 正在进行的成功研究策略，但也将使我们能够启动新的调查途径。第一个 接下来几年的主要目标是对遗传途径有详细的了解 睫状形态多样性已实现。结构上独特的纤毛对于特定的功能至关重要 感觉神经元类型多种物种。尽管现在已经很好地描述了纤毛生成机制，但如何 睫状结构的多样性尚不清楚。我们计划分析产生睫状的机制 秀丽隐杆线虫的形态多样性，也将我们的分析扩展到哺乳动物细胞。第二个主要目标 是为了剖析我们最近的一类新型但保守的热感应分子的特性 描述并探索这些蛋白质如何促进非凡的经验依赖性 感觉神经元类型的热增敏。我们还将研究转录和翻译如何变化 在单个热感应中，神经元类型有助于神经元中的状态和经验依赖性可塑性 电路特性改变热感应行为。一个特别创新的目标是将我们的专业知识结合起来 神经元细胞生物学和刺激诱发的感觉反应的分析系统地描述了如何 感觉活动调节纤毛蛋白组成和神经元功能，相反，探索纤毛 体系结构决定了感官神经元反应谱。根据该综合奖项，我们将能够雇用 我们的多方面实验方法来扩展和加深我们对神经元形式和功能的分析， 结合概念和实验性创新，以建立新的研究方向，并提供更多 综合研究培训经验。纤毛结构和功能的缺陷以及神经元改变 信号传导和可塑性是大量神经系统疾病的基础。考虑到广泛的保护 胶质原性以及哺乳动物和秀丽隐杆线虫之间的神经元途径，我们完全期望从 这项工作将影响和指导与发育和疾病其他生物体的相关研究。