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）：体感系统介导了瘙痒或瘙痒，这是令人不愉快的感觉，引起了人们渴望的渴望。急性瘙痒可以通过警告昆虫，有毒植物或其他刺激物等环境中的有害药物来发挥重要的保护作用。瘙痒也可能是伴随着许多皮肤，系统性和神经系统疾病的令人衰弱的疾病。尽管许多形式的瘙痒是由组胺信号传导介导的，但我们和其他人最近的工作清楚地表明，其他关键的神经途径正在起作用。肥大细胞释放出各种清教元，可介导过敏的瘙痒，牛皮癣和湿疹，抗抗药药并不总是有效地治疗多种过敏性疾病。同样，大多数慢性瘙痒状况对抗组胺药不敏感。对于许多瘙痒疾病，尚未确定治疗的治疗靶点。在对新药物靶标的需求的指示，该提案的目的是识别基于瘙痒的基因和生物分子，重点是原发性传入神经元和脊髓调节性神经元的信号传导机制。体感传入通过瘙痒产生的化合物激活，这些化合物由皮肤中的各种细胞释放。培养基元素通过与G蛋白偶联受体和开放转导通道结合而触发体感神经元激活，从而使神经末端去极化并促进动作电位触发。然后，这些神经元向脊髓中的瘙痒特异性神经元发出信号。尽管最近的研究已经开始描述瘙痒回路的基本特征，但瘙痒的分子机制尚未鉴定出来：在主要传入和脊柱神经元中，受体，转导通道和下游信号传导因素在很大程度上都是未知的。该赠款提案描述了应对这一挑战的新遗传方法的发展。我们是两个生物学家，在感觉神经生物学，遗传学和基因组学方面具有经验和专业知识，他们试图识别驱动瘙痒行为的基因。我们将分析瘙痒诱发行为中遗传上不同小鼠菌株之间的自然变异，并确定构成这种表型变化的序列和基因表达差异。与传统的遗传筛查方法相反，这些方法不容易适用于小鼠中的活动画表型，遗传映射范式具有调查基因组遗传扰动的价值并发现瘙痒的新颖决定因素的潜力。识别候选瘙痒因素将为开发药物和疗法提供了新的靶标，以治疗顽固性瘙痒。呢公共卫生相关性：慢性瘙痒是由多种皮肤疾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。虽然过敏或虫咬伤的瘙痒很容易用抗抗药酶治疗，但大多数形式的慢性瘙痒都对抗组胺治疗具有抵抗力。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发展。