Genetic Mapping of Novel Molecular Players in Itch

瘙痒中新分子参与者的基因图谱

基本信息

批准号：
9437883
负责人：
Diana Michele Bautista
金额：
$ 42.49万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9437883
关键词：
Action Potentials Acute Adverse effects Afferent Neurons Alleles Animals Antihistamines Antimalarials Applications Grants Atopic Dermatitis Basophils Behavior Behavioral Assay Binding Biological Assay Bite Candidate Disease Gene Cells Cellular Assay Ceramides Characteristics Chloroquine Chromosome Mapping Cirrhosis DNA DNA Sequence Development Eczema Esthesia G-Protein-Coupled Receptors Gene Expression Gene Targeting Genes Genetic Genetic Screening Genetic Transcription Genome Genomics Genotype Goals Hormones Hypersensitivity Immune Immunohistochemistry In Situ Hybridization Inbreeding Infiltration Injection of therapeutic agent Interneurons Ion Channel Kidney Failure Lead Lesion Ligands Link Lipids LoxP-flanked allele Malignant Neoplasms Maps Measurement Mediating Methods Modeling Molecular Morphology Mouse Strains Mus Mutant Strains Mice Nerve Neurobiology Neurons Parents Pathway interactions Pharmaceutical Preparations Pharmacology Phenotype Physiological Play Proteins Pruritus Recombinants Regulator Genes Resistance Role Sensory Severities Signal Transduction Signaling Molecule Signaling Protein Skin Spinal Spinal Cord Spinal Ganglia Structure Surveys System Technology Testing Tissues Variant Vitamin D Whole-Cell Recordings behavior measurement behavioral response candidate identification chronic itch dihydroceramide desaturase drug development experience experimental study genetic approach in vivo inorganic phosphate insight keratinocyte live cell imaging mast cell nervous system disorder neuromechanism neuronal excitability neutrophil novel novel therapeutics receptor response skin disorder somatosensory targeted treatment therapy development tool tool development transcription factor transcriptome transcriptome sequencing uptake

项目摘要

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.

抽象的瘙痒被定义为一种不愉快的感觉，会引起抓挠的欲望。相比之下急性瘙痒是短暂的，慢性瘙痒是一种持续的、使人衰弱的病症，治疗选择很少。尽管研究已经确定了许多必需分子转导急性瘙痒信号，我们现在才开始揭示细胞和驱动初级传入神经元和脊髓神经元慢性瘙痒的分子参与者。推进瘙痒治疗技术需要发现分子参与者转导瘙痒感，最终可以作为治疗的目标。该提案的目标是识别潜在的新基因和生物分子痒，重点关注初级传入神经元的信号传导机制，免疫细胞和脊髓调节中间神经元。体感传入是被皮肤中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。瘙痒原通过结合触发体感神经元激活 G 蛋白偶联受体并打开转导通道，使 G 蛋白偶联受体去极化神经末梢并促进动作电位放电；然后这些神经元发出发痒的信号- 脊髓中的特定神经元。虽然最近的研究已经开始描绘痒电路的基本特征，痒的分子机制有尚待确定：受体、转导通道和下游信号传导因素在很大程度上是未知的。该拨款提案描述了新的开发遗传学方法来应对这一挑战。我们是两位经验丰富的生物学家感觉神经生物学、遗传学和基因组学方面的专业知识，致力于识别驱动瘙痒行为的基因。我们将分析遗传之间的自然变异不同的小鼠品系在瘙痒诱发行为中的作用并识别序列和基因这种表型变化背后的表达差异。与传统相比遗传筛查方法不易应用于活体动物表型在小鼠中，遗传作图范式有可能调查基因组的遗传扰动的价值并揭示瘙痒的新决定因素。痒得难以忍受伴随许多皮肤和神经系统疾病，并且在大多数情况下，对抗组胺药治疗不敏感。识别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。