Neurotrophin receptor regulation of taste development

味觉发育的神经营养蛋白受体调节

基本信息

批准号：
8035430
负责人：
Robin Frances Krimm
金额：
$ 26.55万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8035430
关键词：
Adult Afferent Neurons Axon Binding Birth Brain-Derived Neurotrophic Factor Cell Count Cell Cycle Data Development Developmental Process Docking Embryonic Development Epithelium Fiber Fungiform Papilla Genes Genetic Goals Growth Growth Factor Health Immunohistochemistry Injury Intracellular Signaling Proteins Knockout Mice Maintenance Mediating Molecular Mus Mutate NTF3 gene Natural regeneration Nerve Nerve Growth Factor Receptors Nerve Regeneration Nervous System Trauma Neurites Neuronal Differentiation Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Palate Pathway interactions Pattern Peripheral Phospholipase Phosphorylation Site Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Research Role Scanning Electron Microscopy Sensory Sensory Ganglia Signal Pathway Signal Transduction Site System Systems Development Taste Buds Taste Perception Techniques Testing Therapeutic Uses Time Tongue Tyrosine Wild Type Mouse adapter protein axon regeneration improved in vivo nerve supply neuron development neuron loss neuronal survival neurotrophic factor neurotrophin 4 postnatal receptor reinnervation relating to nervous system research study response somatosensory synaptogenesis tool transcriptional coactivator p75

Adult Afferent Neurons Axon Binding Birth Brain-Derived Neurotrophic Factor Cell Count Cell Cycle Data Development Developmental Process Docking Embryonic Development Epithelium Fiber Fungiform Papilla Genes Genetic Goals Growth Growth Factor Health Immunohistochemistry Injury Intracellular Signaling Proteins Knockout Mice Maintenance Mediating Molecular Mus Mutate NTF3 gene Natural regeneration Nerve Nerve Growth Factor Receptors Nerve Regeneration Nervous System Trauma Neurites Neuronal Differentiation Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Palate Pathway interactions Pattern Peripheral Phospholipase Phosphorylation Site Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Research Role Scanning Electron Microscopy Sensory Sensory Ganglia Signal Pathway Signal Transduction Site System Systems Development Taste Buds Taste Perception Techniques Testing Therapeutic Uses Time Tongue Tyrosine Wild Type Mouse adapter protein axon regeneration improved in vivo nerve supply neuron development neuron loss neuronal survival neurotrophic factor neurotrophin 4 postnatal receptor reinnervation relating to nervous system research study response somatosensory synaptogenesis tool transcriptional coactivator p75

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项目摘要

Description (provided by applicant): During development, sensory innervation to taste buds is tightly regulated by the actions of two neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4). Although both of these factors regulate gustatory innervation, their specific functions are different from one another. BDNF is expressed in gustatory epithelium and determines whether gustatory neurons will locate and innervate taste placodes during development, while NT4 does not. Both BDNF and NT4 regulate gustatory neuron and taste bud number, but they have their influences at different times during development. The long range goal of this research is to understand the cellular and molecular mechanisms that regulate the neural innervation to and the maintenance of taste buds during development. The proposed studies focus on mechanisms by which these two neurotrophins, BDNF and NT4, can influence various aspects of neural innervation through the same receptors, TrkB and p75. The proposed studies use cell counting, tract tracing, immunohistochemistry and scanning electron microscopy in gene knockout mice to determine when TrkB and p75 are required for specific aspects of gustatory development, including axonal extension into the tongue, target selection, and geniculate neuron/taste bud survival. Furthermore, these studies combine these anatomical approaches with sophisticated genetic tools allowing the function of single phosphorylation sites on the TrkB receptor protein to be blocked in vivo. These experiments will determine which TrkB intracellular signaling pathways are required for axonal extension into the tongue, target selection, and geniculate neuron/taste bud survival. Together these studies test the hypotheses that TrkB mediates the effects of both BDNF and NT4, but that each function of these neurotrophins requires a different intracellular signaling pathway. While p75's, more subtle role, is to modulate the regulation of gustatory development by neurotrophins. Because these experiments examine the fundamental mechanisms of how neurotrophins regulate neuronal survival and axon targeting via Trk receptors, this project has important implications for the therapeutic use of these signaling mechanisms in controlling neuron survival and axon targeting during regeneration. PUBLIC HEALTH RELEVANCE: The taste system is an ideal and commonly used system for examining axon regeneration following injury. We are examining the signaling mechanisms for two factors (neurotrophins) that influence axon targeting and neuron survival during development. By understanding of how these signaling mechanisms normally function, techniques can be developed to manipulate these important signaling factors during nerve regeneration which will improve reinnervation and function following nervous system injury.

描述（由申请人提供）：在发育期间，对味蕾的感觉神经受到两个神经营养蛋白，脑源性神经营养因子（BDNF）和Neurotrophin-4（NT4）的作用严格调节。尽管这两个因素都调节了味觉神经，但它们的特定功能彼此不同。 BDNF在味觉上皮中表达，并确定味觉神经元在发育过程中是否会定位和支配味道位置，而NT4却没有。 BDNF和NT4都调节了味觉神经元和味蕾，但它们在发育过程中的不同时间都有其影响。这项研究的远距离目标是了解调节神经神经支配以及在发育过程中味蕾的维持的细胞和分子机制。提出的研究重点是这两种神经营养蛋白BDNF和NT4可以通过相同受体TRKB和P75影响神经神经神经神经的各个方面的机制。拟议的研究使用细胞计数，轨道追踪，免疫组织化学和扫描基因敲除小鼠中的电子显微镜来确定味道发育的特定方面何时需要TRKB和p75，包括轴突扩展到舌头，靶标的，靶标的，靶标的和同化神经元/味蕾/味蕾的生存。此外，这些研究将这些解剖方法与复杂的遗传工具结合在一起，从而使TRKB受体蛋白上的单磷酸化位点的功能在体内被阻断。这些实验将确定轴突延伸到舌头，靶标的和统一神经元/味蕾存活需要哪些TRKB细胞内信号通路。这些研究共同检验了TRKB介导BDNF和NT4的影响的假设，但是这些神经营养蛋白的每个功能都需要不同的细胞内信号传导途径。而P75的作用更为微妙，是在调节神经营养蛋白对味觉发育的调节。由于这些实验检查了神经营养蛋白如何通过TRK受体调节神经元存活和轴突靶向的基本机制，因此该项目对这些信号传导机制在控制神经元存活和再生期间的轴突靶向方面具有重要意义。公共卫生相关性：味觉系统是一种理想且常用的系统，用于检查受伤后的轴突再生。我们正在研究影响轴突靶向和发育过程中神经元存活的两个因素（神经营养蛋白）的信号传导机制。通过了解这些信号传导机制通常如何发挥作用，可以开发技术来操纵这些重要的信号传导因子在神经再生过程中，这将改善神经系统损伤后的重新支配和功能。