Genetic Mapping of Novel Molecular Players in Itch

摘要 痒被定义为一种令人不快的感觉，引起了一种渴望抓挠。相比 急性瘙痒是短暂的，慢性瘙痒是一种持续的，使人衰弱的状况， 几种治疗选择。虽然研究已经确定了一些重要的分子 我们现在才刚刚开始揭示细胞和神经系统的作用， 在初级传入神经元和脊髓神经元中驱动慢性瘙痒的分子。 推进瘙痒治疗技术将需要发现分子参与者 这些神经元会刺激感觉，最终可以作为治疗的靶点。 这项提案的目标是确定新的基因和生物分子， 痒，集中在初级传入神经元的信号机制，免疫 细胞和脊髓调节中间神经元。躯体感觉传入神经是 由皮肤中各种细胞释放的致痒化合物激活， 包括角质形成细胞。促瘙痒剂通过与神经元结合而激活躯体感觉神经元 G蛋白偶联受体和开放的转导通道， 神经末梢和促进动作电位放电;这些神经元然后发出信号痒- 脊髓中的特定神经元。虽然最近的研究已经开始描绘 瘙痒回路的基本特征，瘙痒背后的分子机制有 尚未确定：受体、转导通道和下游信号传导 这些因素在很大程度上是未知的。这份赠款提案描述了新的发展 遗传学方法来应对这一挑战。我们是两个有经验的生物学家， 在感觉神经生物学，遗传学和基因组学的专业知识，谁寻求确定 导致瘙痒行为的基因我们将分析基因之间的自然变异 不同品系小鼠瘙痒诱发行为及序列和基因鉴定 表达差异是这种表型变化的基础。与传统的 遗传筛选方法，不容易适用于活体动物表型 在小鼠中，遗传作图范式具有调查基因组的潜力， 并揭示瘙痒的新决定因素。难以忍受的瘙痒 伴随着许多皮肤和神经系统疾病，在大多数情况下， 对抗组胺药治疗不敏感。识别候选瘙痒因子将提供 开发治疗顽固性瘙痒的药物和疗法的新靶点。

ABSTRACT Itch is defined as an unpleasant sensation that evokes a desire to scratch. In contrast to acute itch that is transient, chronic itch is a persistent, debilitating condition, which has few treatment options. Although studies have identified a number of essential molecules that transduce acute itch signals, we are only now beginning to uncover the cellular and molecular players that drive chronic itch in primary afferent neurons and spinal neurons. Advancing treatment technology for itch will require discovery of the molecular players that transduce itch sensations, which can ultimately serve as targets for therapeutics. The goal of this proposal is to identify novel genes and biomolecules that underlie itch, focusing on the signaling mechanisms in primary afferent neurons, immune cells and spinal cord modulatory interneurons. Somatosensory afferents are activated by itch-producing compounds that are released by a variety of cells in the skin, including keratinocytes. Pruritogens trigger somatosensory neuron activation by binding to G-protein coupled receptors and opening transduction channels that depolarize the nerve terminal and promote action potential firing; these neurons then signal to itch- specific neurons in the spinal cord. While recent studies have begun to delineate the basic characteristics of the itch circuit, the molecular mechanisms underlying itch have yet to be identified: the receptors, transduction channels and downstream signaling factors are largely unknown. This grant proposal describes the development of new genetic approaches to meet this challenge. We are two biologists with experience and expertise in sensory neurobiology, genetics, and genomics who seek to identify the genes that drive itch behaviors. We will analyze the natural variation between genetically distinct mouse strains in itch-evoked behaviors and identify sequence and gene expression differences that underlie such phenotypic change. In contrast to traditional genetic screening approaches, which are not easily applicable to live-animal phenotypes in the mouse, the genetic mapping paradigm has the potential to survey a genome's worth of genetic perturbations and uncover novel determinants of itch. Intolerable itch accompanies numerous skin and nervous system disorders, and in most cases, is insensitive to antihistamine treatment. Identification of candidate itch factors will provide new targets for development of drugs and therapies to treat intractable itch.