Neurotrophin receptor regulation of taste development

味觉发育的神经营养蛋白受体调节

• 批准号: 7790695
• 负责人: Robin Frances Krimm
• 金额: $ 27.43万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 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/7790695
• 关键词: Adult; Afferent Neurons; Axon; Binding; Birth; Brain-Derived Neurotrophic Factor; Cell Count; Cell Cycle; Computer Systems Development; Data; Development; Developmental Process; Docking; Embryonic Development; Epithelium; Fiber; Fungiform Papilla; Genes; Genetic; Goals; Growth; Growth Factor; 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; 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; public health relevance; receptor; reinnervation; relating to nervous system; research study; response; somatosensory; synaptogenesis; tool; transcriptional coactivator p75

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）：在发育过程中，味蕾的感觉神经支配受到脑源性神经营养因子（BDNF）和神经营养因子-4 （NT4）两种神经营养因子的作用的严格调节。虽然这两种因素都调节味觉神经支配，但它们的具体功能却各不相同。BDNF在味觉上皮中表达，决定味觉神经元在发育过程中是否会定位和支配味觉基板，而NT4则不会。BDNF和NT4都能调节味觉神经元和味蕾的数量，但在发育过程中它们的作用时间不同。本研究的长期目标是了解味蕾发育过程中神经支配和维持的细胞和分子机制。我们提出的研究重点是BDNF和NT4这两种神经营养因子如何通过TrkB和p75这两种受体影响神经支配的各个方面。拟议的研究在基因敲除小鼠中使用细胞计数、通道示踪、免疫组织化学和扫描电镜来确定TrkB和p75在味觉发育的特定方面何时是必需的，包括轴突延伸到舌头、目标选择和曲状神经元/味蕾存活。此外，这些研究将这些解剖学方法与复杂的遗传工具结合起来，允许在体内阻断TrkB受体蛋白上单个磷酸化位点的功能。这些实验将确定哪些TrkB细胞内信号通路是轴突延伸到舌头、目标选择和膝部神经元/味蕾存活所必需的。这些研究共同验证了TrkB介导BDNF和NT4作用的假设，但这些神经营养因子的每种功能都需要不同的细胞内信号通路。而p75更微妙的作用是通过神经营养因子调节味觉发育。由于这些实验研究了神经营养因子如何通过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机制在再生过程中控制神经元存活和轴突靶向的治疗应用具有重要意义。公共卫生相关性：味觉系统是检查损伤后轴突再生的理想和常用的系统。我们正在研究发育过程中影响轴突靶向和神经元存活的两种因子（神经营养因子）的信号传导机制。通过了解这些信号机制的正常功能，可以开发出在神经再生过程中操纵这些重要信号因子的技术，从而改善神经系统损伤后的神经再生和功能。