Deciphering Trophic Signaling Programs Governing Peripheral Sensory Nervous System Development

破译控制周围感觉神经系统发育的营养信号传导程序

• 批准号: 9887545
• 负责人: Eli Zunder
• 金额: $ 52.63万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9887545
• 关键词: Ablation; Address; Afferent Neurons; Analgesics; Atlases; Behavioral Assay; Brain region; Brain-Derived Neurotrophic Factor; Calibration; Cell Death; Cell Differentiation process; Cell Lineage; Cell Survival; Cells; Coupled; Cytometry; Dancing; Data; Development; Dimensions; Disease model; Dissection; Embryo; Embryonic Development; Environment; Family; Family member; Female; Financial compensation; Fluorescence Microscopy; Goals; Hour; In Vitro; Individual; Logic; Maps; Measurement; Measures; Methods; Modality; Modeling; Molecular; Monitor; Movement Disorders; Mus; Muscle; Mutation; NGFR Protein; Nerve Growth Factor Receptors; Nerve Growth Factors; Nervous system structure; Neural Crest; Neurons; Neurotrophin 3; Nociception; Nociceptors; Organ; Outcome; Pain Disorder; Pain Threshold; Pathway interactions; Perception; Peripheral; Peripheral Nervous System; Phenotype; Play; Population; Positioning Attribute; Proprioception; Proprioceptor; Publishing; Receptor Protein-Tyrosine Kinases; Research; Retina; Role; Sensory; Series; Sex Differences; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Smell Perception; Spinal Cord; Spinal Ganglia; TNF gene; TNFRSF1A gene; Taste Perception; Testing; Time; Tissues; Tumor Necrosis Factor Receptor; Vision; Work; attenuation; behavioral phenotyping; cell type; combinatorial; critical period; design; experience; experimental study; ganglion cell; high dimensionality; in vivo; interest; male; mouse genetics; nerve stem cell; nerve supply; nervous system development; neurotrophic factor; postnatal; postnatal development; programs; receptor; relating to nervous system; response; single cell analysis; small molecule inhibitor; somatosensory; stem cells; time use; treatment strategy

Experiencing a cool breeze or performing an intricate dance step are both realized through a precisely calibrated somatosensory nervous system. How this calibration occurs during nervous system development represents a long-standing question that is fundamental to understanding how we sense our environment. All sensory neurons in the peripheral nervous system (PNS) are derived from a single pool of neural crest progenitor cells, which rapidly differentiate into molecularly distinct classes of neurons in the dorsal root ganglia (DRG), each sensory neuron class responsible for detecting distinct environmental modalities. It has long been assumed that these neurons are pre-programmed to become either nociceptor or proprioceptor, however, our preliminary experiments suggest that final lineage choices of sensory neurons are made after encountering neurotrophic factors derived from target tissues (i.e. skin or muscle). In this proposal, we seek to define how such factors contribute to a trophic signaling axis that drives cell lineage choices. We define this signaling axis or “trophic rheostat” as a soluble target-derived neurotrophic factor, it’s cognate receptor tyrosine kinase, and a synergistic or antagonistic TNFR family member. Our central premise is that differences in the type and/or levels of target-derived trophic signaling drive sensory neuron progenitors toward one of at least 13 terminal cell fates. Our goal is to define the trophic rheostats responsible for each of these developmental choices. To address this idea, we will first map out all cell types in the developing DRG by single cell mass cytometry, measuring at daily timepoints across embryonic and postnatal development to produce a developmental cell atlas of the PNS (Aim1). To determine the influence of trophic signaling rheostats on the differentiation of these cell types, we will investigate the cross-talk and convergence of cell signaling pathways downstream of neurotrophic factor receptors and TNFR family members in vitro (Aim2), and test how perturbing these signaling pathways in vivo influences PNS development and sensory behavioral phenotypes (Aim3). To address these research aims, we are pioneering a combinatorial approach that leverages our expertise in high dimensional single cell analysis, mouse genetics, and neurotrophic signaling, to decipher the trophic signaling rheostats that govern cell differentiation and development in the PNS. We are well positioned to delineate mechanisms that have eluded the field for years. This work will inform our understanding of the development of sensory neurons, rationalizing treatments for the millions of individuals suffering from pain and movement disorders. The mechanisms delineated in this proposal will have broad implications for our understanding of other modalities including taste, audition, olfaction, and vision.

体验凉爽的微风或表演复杂的舞步都是通过精确的 校准的躯体感觉神经系统这种校准在神经系统发育期间如何发生 代表了一个长期存在的问题，对于理解我们如何感知环境至关重要。所有 周围神经系统（PNS）中的感觉神经元来源于单个神经嵴池 在背根神经节中迅速分化成分子上不同类别的神经元的祖细胞 (DRG)每个感觉神经元类负责检测不同的环境模态。人们早就 假设这些神经元预先编程为伤害感受器或本体感受器，然而，我们的研究结果表明， 初步实验表明，感觉神经元的最终谱系选择是在遇到 来源于靶组织（即皮肤或肌肉）的神经营养因子。 在这个建议中，我们试图定义这些因子如何促进营养信号轴，驱动细胞生长， 血统选择我们将这种信号传导轴或“营养变阻器”定义为可溶性靶源性神经营养因子， 因子，它是同源受体酪氨酸激酶，和协同或拮抗TNFR家族成员。我们 核心前提是，目标来源的营养信号的类型和/或水平的差异驱动感觉神经元的功能。 神经元祖细胞朝向至少13种终末细胞命运之一。我们的目标是定义营养变阻器 负责每一个发展的选择。为了解决这个问题，我们将首先绘制出所有细胞类型， 通过单细胞质量细胞术，在胚胎和哺乳动物的每日时间点测量发育中的DRG， 出生后发育，以产生PNS（Aim 1）的发育细胞图谱。确定…的影响 营养信号变阻器对这些细胞类型的分化，我们将研究串扰， 神经营养因子受体和TNFR家族下游细胞信号通路的会聚 成员在体外（Aim 2），并测试如何扰乱这些信号通路在体内影响PNS 发育和感觉行为表型（Aim 3）。 为了实现这些研究目标，我们正在开创一种组合方法， 在高维单细胞分析，小鼠遗传学和神经营养信号传导方面的专业知识，以破译 营养信号变阻器，其控制PNS中的细胞分化和发育。我们完全有能力 来描述这个领域多年来一直回避的机制。这项工作将使我们了解 感觉神经元的发展，使数百万遭受疼痛的人的治疗合理化， 运动障碍本提案中所述的机制将对我们的 对其他形态的理解，包括味觉、听觉、嗅觉和视觉。