NEUROTROPHINS MODULATE SENSORY DEVELOPMENT AND FUNCTION

描述(逐字摘自申请人的摘要)：有相当多的 有证据表明，在许多疼痛状态下，异常的伤害性感受器特性是重要的 影响因素。尤其是增加了伤害性感受器的敏感性，异位 活动生成和改变的中心连接性被认为是关键 疼痛动物模型的变化。这个应用程序测试了这样的假设 在发育过程中或在靶组织中的营养因子表达改变 成虫引起了这些变化。转基因模型将被用于 在皮肤中过度表达NGF或GDNF。这些增长因素支持两个 具有独特生物化学特征的伤害性感受器类别 疼痛路径的差异是其根本原因。具体的目标将考验 以下假设：1)皮肤中表达的GDNF水平调节 特定类型伤害性神经元的存活，2)靶源性神经生长因子和 GDNF独特地调节伤害性神经元的生理特性，并 对疼痛刺激的行为反应，以及3)皮肤来源的营养因子 调控伤害性感受器在特定发育阶段和原因的分化 导致痛觉过敏的成人三叉神经节的变化。GDNF和NGF过表达 转基因小鼠及Cre调控NGF表达的新诱导模型 重组酶的表达将用于检测伤害性感受器的依赖性 胶质细胞源性神经营养因子和神经生长因子的神经元发育、分化和功能特性 由皮肤产生。原位杂交、免疫组织化学、行为学 测试、神经元计数、RT-PCR和电生理学将用于 检测神经生长因子和胶质细胞源性神经营养因子依赖的表型和生理特性 伤害性感受器来确定它们在化学表型上可能如何重叠和不同， 受体表达、生理特性与外周和中枢 投影图案。这里提出的研究带来了一个多学科的 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人的伤害性感受功能。定义 这两组伤害性感受器的功能特性将是重要的 以了解成年人正常和异常的伤害性感受器活动。通过 探索这些问题，我们将提供基本发展的答案 同样适用于外周和中枢神经系统的问题 为多种疾病的治疗提供了基础 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.