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

描述（由申请人提供）：主干中伤害感觉（疼痛转导）的神经回路的建立和正常生理功能的机制已知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）和胶质细胞系衍生的神经营养因子（GDNF）家族配体（GFLs）至关重要。NGF和GFLs通过各自的受体酪氨酸激酶TrkA和Ret发出信号，支持主干中功能不同的伤害感受器的发展。此外，NGF和GFLs还需要获得定义每种伤害感受器群体功能特征的分子特性，以及这些神经元的出生后维持。然而，目前尚不清楚NGF-TrkA和GFL-Ret信号是否在三叉神经伤害感受器的发育中起到类似的作用，三叉神经伤害感受器在许多方面在分子和功能上与主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p75，一种TrkA共受体的作用

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.