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Molecular Mechanisms of Trigeminal Development

三叉神经发育的分子机制

基本信息

批准号：
7760928
负责人：
MARK F JACQUIN
金额：
$ 87.94万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7760928
关键词：
Molecular Mechanisms Trigeminal Development

项目摘要

Ongoing collaborations between neuroscientists at the Washington University School of Medicine, Medical College,of Ohio, and Louisiana State University will reveal molecular mechanisms that control the development of mammalian sensory systems. The trigeminal (V) system, inclusive of the whisker-to-barrel pathway, will be used as a model to test hypotheses pertaining to: 1) chemotropic and synaptotrophic actions of neurotrophins in the differentiation of primary afferent neurons; 2) neurotrophic actions upon pattern formation in primary afferents; 3) actions of suspected axon guidance molecules (neurotrophins, Slits, others) in V axon development; 4) transcriptional mechanisms of primary afferent and second-order neuron development; 5) mechanisms by which serotonin and ephrins control thalamocortical axon growth. This renewal application focuses on mechanisms of axon and cell development in the rodent somatosensory periphery and in the brain pathways that conduct somatosensory information. It builds on unparalleled expertise in studies of the V system and adds powerful new approaches from molecular biology. There are 4 Projects and 2 Cores: Project 1 will evaluate the role of the neurotrophins NGF, NTS and GDNF family ligands in peripheral and central branching and functional connectivity of V ganglion cells; it exploits knockouts of NGF, NTS or GDNF and a proapoptotic gene (bax) to test the hypothesis that these molecules have specific tropic effects on the branching patterns of V ganglion cells. Project 2 will evaluate the role of axon guidance molecules (Slits, and their Robo receptors) in the formation of connections between the whiskerpad, V ganglion, V brainstem nuclei and somatosensory thalamus. Project 3 builds on the important new finding that certain transcription factors are necessary for specifying the central targets of the V ganglion (the V brainstem complex), and that this specification is reflected in thalamic and cortical development. It is hypothesized that Lmxlb controls a cascade of downstream genes, in addition to Drg11. Project 4 tests the hypothesis that ephrin/Eph interactions form boundaries within and around the cortical whisker-barrel field that determine the morphology of developing thalamocortical axons both in normal development and when such morphologies are perturbed by elevated serotonin levels in the cortex. Core A will provide molecular biology oversight/expertise, electron microscopy, stereology, pattern analyses, statistical oversight/expertise, administrative support, peer review, and ensure timely communication between projects. Core B will selectively label V axons in embryonic mice and provide standardized and unbiased tissue processing, microscopic evaluations and documentation of these axonal projections.

华盛顿大学医学院、俄亥俄州医学院和路易斯安那州立大学的神经科学家正在进行的合作将揭示控制哺乳动物感觉系统发育的分子机制。三叉神经（V）系统，包括须-桶神经营养因子在初级传入神经元分化过程中的趋化性和突触营养作用; 2）初级传入神经元模式形成过程中的神经营养作用; 3）疑似轴突导向分子的作用（神经营养因子，Slits等）在V轴突发育中的作用; 4）初级传入和二级神经元发育的转录机制; 5）5-羟色胺和ephrin控制丘脑皮质轴突生长的机制。这种更新的应用程序集中在轴突和细胞发育的啮齿动物躯体感觉外周和大脑通路，进行躯体感觉信息的机制。它建立在V系统研究的无与伦比的专业知识基础上，并从分子生物学中增加了强大的新方法。有4个项目和2个核心：项目1将评估神经营养因子NGF、NTS和GDNF家族配体在V神经节细胞的外周和中枢分支和功能连接中的作用;它利用NGF、NTS或GDNF和促凋亡基因（bax）的敲除来测试这些分子对V神经节细胞的外周和中枢分支和功能连接具有特异性向性作用的假设。 V神经节细胞的分支模式。项目2将评估轴突导向分子（Slits及其Robo受体）在whiskerpad，V神经节，V脑干核和体感丘脑之间连接形成中的作用。项目3建立在重要的新发现基础上，即某些转录因子对于指定V神经节（V脑干复合体）的中心目标是必要的，并且这种指定反映在丘脑和皮质发育中。假设Lmxlb控制下游基因的级联，除了Drg 11。项目4测试的假设，肝配蛋白/Eph相互作用形成的边界内和周围的皮质须桶场，确定的形态发育中的丘脑皮质轴突在正常的发展，当这种形态受到干扰的皮质中的血清素水平升高。核心A将提供分子生物学监督/专业知识、电子显微镜、体视学、模式分析、统计监督/专业知识、行政支持、同行评审，并确保项目之间的及时沟通。核心B将选择性地标记胚胎小鼠中的V轴突，并提供标准化的、无偏的组织处理、显微镜评价和这些轴突投射的记录。