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

基本信息

批准号：
8867869
负责人：
Christopher Ryan Donnelly
金额：
$ 4.89万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/8867869
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 neuronal circuitry neurotrophic factor novel painful neuropathy postnatal public health relevance receptor research study skills therapeutic target transcriptional coactivator p75

项目摘要

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）：已知躯干伤害感受（疼痛传导）神经回路的建立和正常生理功能的机制需要促进生存和生长的神经营养因子，其中神经生长因子（ NGF）和神经胶质细胞源性神经营养因子（GDNF）配体家族（GFL）至关重要。 NGF 和 GFL 通过各自的受体酪氨酸激酶 TrkA 和 Ret 发出信号，支持躯干中功能不同的伤害感受器的发育。此外，NGF 和 GFL 还需要获取定义每个伤害感受群体功能特征的分子特性，以及这些神经元的出生后维护。然而，目前尚不清楚 NGF-TrkA 和 GFL-Ret 信号传导在三叉神经伤害感受器的发育中是否发挥类似作用，三叉神经伤害感受器在许多方面在分子和功能上与躯干中的伤害感受器不同。这里提出的实验的第一个目标是确定 TrkA 辅助受体 p75 的作用以及 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。第二个目标是确定三叉神经伤害感受器的生存及其对牙髓的神经支配需要多大程度的 NGF-TrkA 和 GFL-Ret 信号传导，牙髓是接受纯粹伤害性神经支配的重要三叉神经目标。总的来说，考虑到 NGF 和 GDNF 在伤害性回路发育过程中作为生存和生长介质的既定作用，以及越来越多的证据表明这些因素作为痛觉过敏和机械性异常性疼痛的介质，这里提出的实验可能具有重要意义。对合理设计旨在对抗慢性疼痛的治疗策略的影响。