Morphogenesis of the peripheral sensory nervous system

周围感觉神经系统的形态发生

• 批准号: 7471988
• 负责人: MARK M VOIGT
• 金额: $ 15.42万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7471988
• 关键词: AIDS/HIV problem; Adopted; Adult; Affect; Afferent Neurons; Age; Alleles; Animal Model; Cephalic; Clinical; Collaborations; Condition; Country; Data; Defect; Development; Diabetes Mellitus; Disease; Embryo; Engineering; Ethylnitrosourea; Exhibits; Face; Family; Fishes; Functional disorder; Future; Ganglia; Gene Expression; Genes; Genetic; Genetic Programming; Genetic Screening; Genome; Goals; Head; Health; Healthcare Systems; Hereditary Sensory Neuropathy; Human Resources; Individual; Investments; Malignant Neoplasms; Mediating; Modality; Modeling; Morphogenesis; Mutagenesis; Mutate; Mutation; Myxoid cyst; Nervous system structure; Neuroblastoma; Neurons; Neuropathy; Nociception; Numbers; Operative Surgical Procedures; Organism; Outcome; Pattern; Peripheral; Peripheral Nervous System Diseases; Population; Process; Proprioception; Proteins; Public Health; Quality of life; Rate; Resources; Screening procedure; Sensory; Sensory Disorders; Sensory Ganglia; Signal Pathway; Signal Transduction; Structure of trigeminal ganglion; Taste Perception; Time; Tissues; Transgenic Organisms; Trauma; Trigeminal Neuralgia; Viscera; Week; Work; Zebrafish; attenuation; base; design; human disease; insight; interest; mutant; myelination; nerve supply; neurodevelopment; neuronal cell body; novel strategies; novel therapeutics; programs; sensory neuropathy; size; small molecule; therapeutic target; tool

DESCRIPTION (provided by applicant): There are numerous clinical conditions in which altered sensory signaling from the face, head and/or viscera are manifested, e.g. peripheral neuropathies arising from diabetes, HIV/AIDS and herpes, trigeminal neuralgia, the various hereditary sensory neuropathies, neuropathies arising from trauma or surgical outcomes, and others. We have recently engineered a transgenic fish line that expresses an eGFP marker protein in neurons of the cranial sensory ganglia (CSG). The eGFP produced is soluble and fills the cell body together with its peripheral and central projections. This expression begins at the time these neurons are forming the ganglia and extending their axonal processes, and is maintained through at least three weeks of age. We propose using these transgenic fish in a ethylnitrosourea-based mutagenesis screen in an effort to identify genes involved in any of the following three processes: formation of the individual cranial ganglia, innervation of specific targets by different ganglia, and innervation of different targets by individual neurons within the same ganglia. There are two aims for the work proposed in this application: (1) to introduce ENU mutated genes into the TG(3.2::eGFPGR) line and use an F3 recessive screening paradigm to identify carrier families that produce embryos exhibiting defects in CSG development and connectivities and (2) to characterize the identified mutants. We have initiated a preliminary screen using a small number of carrier families (21). To date, we have already identified two mutants (out of 11 families screened) that have developmental abnormalities in their CSG by 96 hpf. Allele sl14 exhibits disrupted formation of the trigeminal ganglia while having normal epibranchial ganglia, whereas allele sl19 has improper targeting of the central and peripheral projections of the epibranchial ganglia while the trigeminal ganglia appear unaltered. This R21 proposal is designed to increase the size of our screen to 150-200 families (genomes) in order to generate a body of mutants that cover the wide spectrum of mechanisms responsible for CSG formation. A successful outcome of this proposal will also strengthen a nascent collaboration between the Voigt lab (SLU), which is focused on peripheral neurons and signaling issues and is adopting zebrafish as a model, and the Appel lab (Vanderbilt), an established zebrafish lab which is interested in mechanisms underlying the myelination of central and peripheral neurons. PUBLIC HEALTH RELEVANCE Millions of people worldwide suffer degraded health and quality of life issues due to peripheral sensory neuropathies. Currently, treatment of such disorders is limited by the lack of clinically useful tools. The principal goal of this project is to provide a springboard for the development of new approaches to the treatment of these diseases by identifying genes, and thus potential therapeutic targets, involved in the normal development of the sensory nervous system.

描述（由申请人提供）：存在许多临床病症，其中表现出来自面部、头部和/或内脏的感觉信号改变，例如由糖尿病、HIV/AIDS和疱疹引起的周围神经病、三叉神经痛、各种遗传性感觉神经病、由创伤或手术结果引起的神经病等。我们最近设计了一种转基因鱼线，表达的eGFP标记蛋白的神经元的颅感觉神经节（CSG）。产生的eGFP是可溶的，并填充细胞体及其外周和中央突起。这种表达开始于这些神经元形成神经节并延伸其轴突过程的时候，并维持至少三周的年龄。我们建议使用这些转基因鱼在一个乙基亚硝基脲为基础的诱变筛选，以确定参与以下三个过程中的任何一个的基因：形成的个人颅神经节，神经支配的特定目标由不同的神经节，神经支配的不同目标由个别神经元在同一神经节。本申请中提出的工作有两个目的：（1）将ENU突变基因引入TG（3.2：：eGFPGR）系中，并使用F3隐性筛选范例来鉴定产生表现出CSG发育和连接性缺陷的胚胎的携带者家族，和（2）表征鉴定的突变体。我们已经使用少量携带者家族启动了初步筛查（21）。到目前为止，我们已经确定了两个突变体（11个家庭筛选），有发展异常的CSG的96 hpf。等位基因s114表现出三叉神经节的破坏形成，同时具有正常的鳃上神经节，而等位基因s119具有不适当的靶向的中央和外周投影的鳃上神经节，而三叉神经节出现不变。这个R21的建议是为了增加我们的屏幕的大小到150-200个家庭（基因组），以产生一个机构的突变体，涵盖了广泛的机制负责CSG的形成。这一提议的成功结果也将加强Voigt实验室（SLU）和阿佩尔实验室（范德比尔特）之间的初步合作，该实验室专注于外周神经元和信号传导问题，并采用斑马鱼作为模型，该实验室是一个成熟的斑马鱼实验室，对中枢和外周神经元髓鞘形成的机制感兴趣。公共卫生相关性全世界有数百万人因周围感觉神经病变而遭受健康和生活质量下降的问题。目前，这种疾病的治疗受到缺乏临床有用工具的限制。该项目的主要目标是通过识别参与感觉神经系统正常发育的基因，从而为开发治疗这些疾病的新方法提供一个跳板。