Genetic Mapping of Novel Molecular Players in Itch

摘要 瘙痒被定义为一种令人不快的感觉，引起抓挠的欲望。与之形成鲜明对比的是 急性瘙痒是一过性的，慢性瘙痒是一种持续性的、使人虚弱的状况，它有 治疗选择很少。尽管研究已经确定了一些必要的分子 我们现在才开始发现细胞和 在初级传入神经元和脊髓神经元中驱动慢性瘙痒的分子玩家。 推进瘙痒治疗技术将需要发现分子作用者 它传递瘙痒感觉，最终可以作为治疗的靶点。 这项提议的目标是识别新的基因和生物分子。 瘙痒，主要研究初级传入神经元的信号机制，免疫 细胞和脊髓调制中间神经元。体感传入是 由皮肤中的各种细胞释放的产生瘙痒的化合物激活， 包括角质形成细胞。促性腺激素通过结合触发体感神经元激活 G蛋白偶联受体和开放的信号转导通道，使细胞去极化 神经末梢和促进动作电位放电；然后这些神经元向瘙痒- 脊髓中的特定神经元。虽然最近的研究已经开始描绘出 瘙痒回路的基本特征，瘙痒的分子机制有 尚未确定：受体、转导通道和下游信号 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 基因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、遗传学和基因组学方面的专业知识，他们试图识别 驱动瘙痒行为的基因。我们将分析基因上的自然变异 不同品系小鼠的瘙痒行为特征及序列和基因鉴定 表达差异是这种表型变化的基础。与传统的 不易应用于活体动物表型的遗传筛选方法 在小鼠中，遗传图谱范例有可能调查基因组的 基因扰动的价值和发现瘙痒的新决定因素。无法忍受的瘙痒 伴随着大量的皮肤和神经系统疾病，在大多数情况下， 对抗组胺药物治疗不敏感。确定候选瘙痒因素将提供 开发治疗顽固性瘙痒的药物和疗法的新目标。

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.