Genetic Mapping Of Novel Molecular Players in Itch

痒痒中新分子参与者的基因图谱

基本信息

批准号：
8386457
负责人：
Diana Michele Bautista
金额：
$ 23.03万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8386457
关键词：
Action Potentials Acute Afferent Neurons Allergic Animals Antihistamines Applications Grants Behavior Behavioral Behavioral Assay Binding Biological Assay Bite Cells Characteristics Cheek structure Chromosome Mapping Chronic Cirrhosis Clinic DNA Sequence Data Detection Development Disease Drug Delivery Systems Eczema Environment Esthesia G-Protein-Coupled Receptors Gene Expression Gene Structure Genes Genetic Genetic Screening Genome Genomics Genotype Goals Histamine Hypersensitivity Inbred DBA Mice Inbreeding Injection of therapeutic agent Insecta Interneurons Irritants Kidney Failure Lead Life Light Malignant Neoplasms Maps Mediating Messenger RNA Methods Molecular Mouse Strains Mus Mutagenesis Nature Nerve Neural Pathways Neurobiology Neurons Parents Pathway interactions Pharmacotherapy Phenotype Play Pruritus Psoriasis Quantitative Trait Loci RNA Recombinants Regulator Genes Resistance Role Sensory Signal Transduction Skin Spinal Spinal Cord Spinal Ganglia Stimulus Surveys System Technology Toxic Plants Transcript Variant Work candidate identification experience insight mast cell meetings nervous system disorder neuromechanism novel receptor response skin disorder somatosensory therapeutic target tool development

项目摘要

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.

描述（由申请人提供）：体感系统介导瘙痒或瘙痒，即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（例如昆虫、有毒植物或其他刺激物）发挥重要的保护作用。瘙痒症也可能是一种使人衰弱的疾病，伴有多种皮肤、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清楚地表明，其他关键神经通路也在发挥作用。肥大细胞释放多种净化原，介导过敏引起的瘙痒、牛皮癣和湿疹，而抗组胺药并不总是能有效治疗所有过敏性疾病。同样，大多数慢性瘙痒症状对抗组胺药治疗不敏感。对于许多瘙痒症，治疗靶点尚未确定。在鉴于对新药物靶点的需求，该提案的目标是识别引起瘙痒的基因和生物分子，重点关注初级传入神经元和脊髓调节中间神经元的信号传导机制。体感传入神经由皮肤多种细胞释放的致痒化合物激活。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体感神经元激活，从而使神经末梢去极化并促进动作电位放电；然后，这些神经元向脊髓中特定于瘙痒的神经元发出信号。虽然最近的研究已经开始描述瘙痒回路的基本特征，但瘙痒背后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。该拨款提案描述了应对这一挑战的新遗传方法的开发。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，他们致力于识别驱动瘙痒行为的基因。我们将分析遗传不同的小鼠品系在瘙痒诱发行为方面的自然变异，并识别导致这种表型变化的序列和基因表达差异。与不易应用于小鼠活体动物表型的传统遗传筛查方法相比，遗传作图范式有可能调查基因组的遗传扰动价值并发现新的瘙痒决定因素。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：慢性瘙痒是由多种皮肤病和全身性疾病引起的，例如湿疹、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有助于开发急需的新型药物和疗法。