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: 10320349
• 负责人: Eli Zunder
• 金额: $ 51.2万
• 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/10320349
• 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.

体验微风或表演复杂的舞步，都可以通过一个精确地实现 校准体感神经系统。这种校准是如何在神经系统发展过程中发生的 代表了一个长期存在的问题，这对于理解我们如何感知环境至关重要。全部 周围神经系统（PN）中的感觉神经元源自单个神经元库 祖细胞在背根神经节中迅速分化为分子不同的神经元类别 （DRG），每个感觉神经元类别负责检测不同的环境方式。长期以来已经 假设这些神经元被预先编程为伤害感受器或本体受体，但是，我们 初步实验表明，遇到感觉神经元的最终谱系选择 源自目标时机（即皮肤或肌肉）的神经营养因子。 在此提案中，我们试图定义此类因素如何促进驱动细胞的营养信号轴 血统选择。我们将此信号轴或“营养风湿病”定义为可溶性靶向衍生的神经营养 因素，是同源受体酪氨酸激酶，以及协同或拮抗的TNFR家族成员。我们的 中心前提是目标衍生的营养信号传导感觉的类型和/或水平的差异 神经元祖细胞至少13个末端细胞命运之一。我们的目标是定义营养变变 负责这些发展选择中的每一个。为了解决这个想法，我们将首先绘制所有单元类型 通过单细胞质量细胞仪的开发DRG，在跨胚胎和 产生后发育以产生PNS的发育细胞图集（AIM1）。确定 营养信号传导风湿病在这些细胞类型的分化方面，我们将研究串扰和 神经营养因子受体和TNFR家族下游细胞信号通路的收敛性 体外成员（AIM2），并测试体内这些信号传导途径如何影响PNS 发展和感觉行为表型（AIM3）。 为了解决这些研究的目的，我们正在开创一种利用我们的组合方法 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 支配PN中细胞分化和发育的营养信号变阻器。我们的位置很好 描绘了多年来一直避开该领域的机制。这项工作将为我们了解 感官神经元的发展，对数百万患有痛苦和 运动障碍。该提案中描述的机制将对我们的 了解其他方式，包括口味，试听，嗅觉和视觉。