NEUROTROPHINS MODULATE SENSORY DEVELOPMENT AND FUNCTION

描述（来自申请人摘要的逐字）： 证据表明，在许多疼痛状态下，异常的伤害感受器特性是重要的 促成因素。特别是，增加的伤害感受器敏感性，异位 活动的产生和改变的中央连接被认为是关键 疼痛动物模型的变化。本申请检验了以下假设： 在发育过程中靶组织中营养因子表达的改变， 成年人引起了这些变化。将使用转基因模型， 在皮肤中过度表达NGF或GDNF。这些增长因素支持两个 具有独特生化特征的伤害感受器类别， 疼痛通路的差异。具体目标将测试 以下假设：1）GDNF在皮肤中的表达水平调节了皮肤的生长， 特定类型的伤害感受神经元的存活，2）靶源性NGF，以及 GDNF独特地调节伤害感受神经元的生理特性， 对疼痛刺激的行为反应; 3）皮肤源性营养因子 在特定的发育阶段调节伤害感受器的分化， 导致痛觉过敏的成年PNS的变化。GDNF和NGF过表达 转基因小鼠和一种新的Cre调控的神经生长因子表达诱导模型 重组酶的表达将被用来检测伤害感受器的依赖性 神经元发育、分化和功能特性对GDNF和NGF的影响 由皮肤产生。原位杂交，免疫组织化学，行为 测试，神经元计数，RT-PCR和电生理学将用于 研究NGF和GDNF依赖性的表型和生理特性， 伤害感受器以确定它们如何在化学表型上重叠和不同， 受体表达、生理特性以及外周和中枢 投射模式这里提出的研究带来了多学科的 了解NGF和GDNF如何塑造发育中的感觉系统的方法 以及它们如何继续调节成年人的伤害感受功能。限定 这两组伤害感受器的功能特性将是重要的 了解成年人正常和异常的伤害感受器活动。通过 探索这些问题，我们将提供基本的发展答案， 适用于外周和中枢神经系统的问题，以及 为开发治疗各种疾病的方法提供了基础， 疼痛起主要作用的疾病状态。

DESCRIPTION (Verbatim from the Applicant's Abstract): There is considerable evidence that in many pain states, abnormal nociceptor properties are important contributing factors. In particular, increased nociceptor sensitivity, ectopic activity generation, and altered central connectivity are recognized as key changes in animal models of pain. This application tests the hypothesis that altered trophic factor expression in the target tissue during development or in the adult induces these changes. Transgenic models will be used that overexpress either NGF or GDNF in the skin. These growth factors support two classes of nociceptors with unique biochemical characteristics that may underlie differences in pain pathways. The Specific Aims will test the following hypotheses: 1) the level of GDNF expressed in skin regulates the survival of specific types of nociceptive neurons, 2) target-derived NGF and GDNF uniquely regulate the physiological properties of nociceptive neurons and behavioral response to painful stimuli, and 3) skin-derived trophic factors regulate nociceptor differentiation at specific stages of development and cause changes in the adult PNS that lead to hyperalgesia. GDNF and NGF overexpresser transgenic mice and a new inducible model of NGF expression regulated by Cre recombinase expression will be used to examine the dependence of nociceptor neuron development, differentiation, and functional properties on GDNF and NGF produced by the skin. In situ hybridization, immunohistochemistry, behavioral testing, neuronal counting, RT-PCR, and electrophysiology will be used to examine phenotypic and physiologic properties of NGF- and GDNF-dependent nociceptors to determine how they may overlap and differ in chemical phenotype, receptor expression, physiologic properties and peripheral and central projection patterns. The studies proposed here bring a multidisciplinary approach to understanding how NGF and GDNF sculpt the developing sensory system and how they continue to modulate nociceptive function in the adult. Defining the functional properties of these two groups of nociceptors will be important for understanding normal and abnormal nociceptor activity in the adult. By exploring these issues we will be providing answers to basic developmental questions applicable to both the peripheral and central nervous system, as well as providing the foundation for development of therapies for a wide range of disease states in which pain plays a major role.