Genetic Mapping Of Novel Molecular Players in Itch

描述（由申请人提供）：躯体感觉系统介导瘙痒或瘙痒，这是一种引起抓挠欲望的不愉快感觉。急性瘙痒症通过警告环境中的有害物质如昆虫、有毒植物或其他刺激物而起到重要的保护作用。瘙痒也可以是一种衰弱的条件，伴随着许多皮肤，全身和神经系统疾病。虽然许多形式的瘙痒是由组胺信号介导的，但我们和其他人最近的工作表明，其他关键的神经通路也在起作用。肥大细胞释放多种净化剂，介导过敏诱发的瘙痒、银屑病和湿疹，抗组胺药在治疗过敏性疾病的全谱方面并不总是有效的。同样，大多数慢性瘙痒症状对抗组胺药治疗不敏感。对于许多瘙痒病症，用于治疗的治疗靶标尚未确定。在 鉴于需要新的药物靶点，本提案的目标是鉴定引起瘙痒的基因和生物分子，重点是初级传入神经元和脊髓调节中间神经元中的信号传导机制。躯体感觉传入由皮肤中的各种细胞释放的产生瘙痒的化合物激活。瘙痒原通过与G蛋白偶联受体结合并打开转导通道来触发躯体感觉神经元激活，所述转导通道使神经末梢脱髓鞘并促进动作电位放电;这些神经元然后向脊髓中的瘙痒特异性神经元发出信号。虽然最近的研究已经开始描绘瘙痒回路的基本特征，但瘙痒的分子机制尚未确定：初级传入神经元和脊髓神经元中的受体、转导通道和下游信号传导因子在很大程度上是未知的。这项拨款提案描述了新的遗传方法的发展，以迎接这一挑战。我们是两位在感觉神经生物学、遗传学和基因组学方面拥有丰富经验和专业知识的生物学家，他们试图识别驱动瘙痒行为的基因。我们将分析遗传上不同的小鼠品系在瘙痒诱发行为中的自然变异，并确定这种表型变化背后的序列和基因表达差异。与传统的遗传筛选方法，这是不容易适用于活的动物表型的小鼠，遗传作图范式有可能调查基因组的遗传扰动的价值，并发现新的瘙痒的决定因素。识别候选瘙痒因素将 为开发治疗顽固性瘙痒的药物和疗法提供新的靶点。! 公共卫生相关性：慢性瘙痒是由许多皮肤病和全身性疾病引起的，如湿疹、肾衰竭、肝硬化和一些癌症。虽然过敏或虫咬引起的瘙痒很容易用抗组胺药治疗，但大多数形式的慢性瘙痒对抗组胺药治疗有抵抗力。了解引起急性和慢性瘙痒的神经机制可能会导致急需的新型药物和疗法的开发。

DESCRIPTION (provided by applicant): The somatosensory system mediates pruritus, or itch, the unpleasant sensation that evokes a desire to scratch. Acute pruritus serves an important protective function by warning against harmful agents in the environment such as insects, toxic plants or other irritants. Pruritus can also be a debilitating condition that accompanies numerous skin, systemic, and nervous system disorders. While many forms of itch are mediated by histamine signaling, recent work by us and others makes clear that additional key neural pathways are at play. Mast cells release a variety of puritogens that mediate allergy-evoked itch, psoriasis and eczema, and anti-histamines are not always effective in treating the full spectrum of allergic disorders. Likewise, most chronic itch conditions are insensitive to antihistamine treatment. For many itch disorders, therapeutic targets for treatment have yet to be identified. In light of the need for novel drug targets, the goal of this proposal is to identify genes and biomolecules that underlie itch, focusing on signaling mechanisms in primary afferent neurons and spinal cord modulatory interneurons. Somatosensory afferents are activated by itch-producing compounds that are released by a variety of cells in the skin. 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, in both primary afferents and spinal neurons. 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. Identification of candidate itch factors will provide new targets for development of drugs and therapies to treat intractable itch. ! PUBLIC HEALTH RELEVANCE: Chronic itch results from of a number of skin diseases and systemic conditions, such as eczema, kidney failure, cirrhosis and some cancers. While itch from allergies or bug bites is readily treatable with anti-histamines, most forms of chronic itch are resistant to antihistamine treatment. Understanding the neural mechanisms that evoke acute and chronic itch may lead to the development of much needed, novel drugs and therapies.