Understanding the Function of GFL-Ret Signaling in the Development of the Periphe

了解 GFL-Ret 信号在外周发育中的功能

• 批准号: 8716461
• 负责人: Christopher Ryan Donnelly
• 金额: $ 4.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716461
• 关键词: Affect; Afferent Neurons; Animal Model; Cessation of life; Characteristics; Clinical; Complex; Critical Thinking; Dental Pulp; Development; Family; Future; GDNF gene; Goals; Grant; Growth; Growth Factor; Histologic; Human; Hyperalgesia; Knockout Mice; Knowledge; Laboratories; Ligands; Maintenance; Mediator of activation protein; Molecular; Nerve Growth Factors; Neurobiology; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 1; Nociception; Nociceptors; Pain; Patients; Peripheral; Physiological; Population; Property; Receptor Protein-Tyrosine Kinases; Research; Role; Scientist; Sensory; Signal Transduction; Specific qualifier value; Spinal Ganglia; Survival Analysis; TNF gene; Testing; Therapeutic; Thermal Hyperalgesias; Tooth structure; Training; Trigeminal System; Work; base; behavior test; career; chronic pain; combat; craniofacial; design; expectation; glial cell-line derived neurotrophic factor; insight; knowledge base; mechanical allodynia; member; nerve supply; neural circuit; neurotrophic factor; novel; painful neuropathy; postnatal; public health relevance; receptor; research study; skills; therapeutic target; transcriptional coactivator p75

DESCRIPTION (provided by applicant): The mechanisms underlying the establishment and normal physiological function of the neural circuits underlying nociception (the transduction of pain) in the trunk are known to require survival- and growth- promoting neurotrophic factors, of which nerve growth factor (NGF) and the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs) are critical. NGF and the GFLs support the development of functionally distinct nociceptors in the trunk by signaling through their respective receptor tyrosine kinases, TrkA and Ret. In addition, NGF and the GFLs are also required for the acquisition of the molecular properties that define the functional characteristics of each nociceptive population, as well as the postnatal maintenance of these neurons. It is unknown, however, whether NGF-TrkA and GFL-Ret signaling serve an analogous role in the development of trigeminal nociceptors, which are, in many ways, molecularly and functionally distinct from nociceptors in the trunk. The first objective of the experiments proposed here is to identify the role of p75, a TrkA co-receptor and a novel constituent of the GFL-Ret receptor complex, in the development and physiological function of dorsal root ganglion (DRG) sensory neurons and their peripheral projections. The second objective is to identify to what extent NGF-TrkA and GFL-Ret signaling are required for the survival of trigeminal nociceptors and their innervation of the tooth pulp, an important trigeminal target receiving purely nociceptive innervation. Collectively, given the well-establishe role of NGF and GDNF as mediators of survival and growth during nociceptive circuit development, and the emerging body of evidence suggesting these factors serve as mediators of hyperalgesia and mechanical allodynia, the experiments proposed here are likely to have important implications for the rational design of therapeutic strategies seeking to combat chronic pain.

描述（由申请人提供）：已知躯干中伤害感受（疼痛转导）神经回路的建立和正常生理功能的机制需要促进存活和生长的神经营养因子，其中神经生长因子（NGF）和神经胶质细胞系衍生的神经营养因子（GDNF）配体家族（GFL）是关键。NGF和GFLs通过其各自的受体酪氨酸激酶TrkA和Ret的信号传导支持躯干中功能不同的伤害感受器的发育。此外，NGF和GFLs也是获得定义每个伤害感受群体的功能特征的分子特性以及这些神经元的出生后维持所必需的。然而，NGF-TrkA和GFL-Ret信号传导是否在三叉神经伤害感受器的发育中起类似的作用尚不清楚，三叉神经伤害感受器在许多方面与躯干中的伤害感受器在分子和功能上不同。本文提出的实验的第一个目的是鉴定p75（TrkA共受体）的作用。 和GFL-Ret受体复合物的新成分，在背根神经节（DRG）感觉神经元及其外周投射的发育和生理功能中的作用。第二个目的是确定NGF-TrkA和GFL-Ret信号传导在多大程度上是三叉神经伤害感受器及其牙髓神经支配的存活所需的，牙髓是接受纯粹伤害性神经支配的重要三叉神经靶点。总的来说，由于NGF和GDNF在伤害性回路发育过程中作为生存和生长介质的良好作用，以及新出现的证据表明这些因素作为痛觉过敏和机械异常性疼痛的介质，这里提出的实验可能对寻求对抗慢性疼痛的治疗策略的合理设计具有重要意义。