Neurotrophin mechanisms in neural development and disease

神经营养蛋白在神经发育和疾病中的机制

基本信息

批准号：
8322573
负责人：
Rejji Kuruvilla
金额：
$ 34.98万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8322573
关键词：
Address Adult Axon Biochemical Biological Biological Assay Calcineurin Calcium Cues Development Disease Dominant-Negative Mutation Endocytosis Event Family Foundations Future Goals Growth Growth Factor Guanosine Triphosphate Phosphohydrolases Hand Image In Vitro Injury Knockout Mice Link Mediating Molecular Mus Mutant Strains Mice Nerve Growth Factors Nervous System Physiology Nervous System Trauma Nervous system structure Neurodegenerative Disorders Neurons Neurotrophic Tyrosine Kinase Receptor Type 1 Neurotrophin 3 Organ Pathway interactions Peripheral Phase Phospholipase Phosphoric Monoester Hydrolases Physiological Protein Isoforms Protein Serine/Threonine Phosphatase RNA Splicing Reporting Research Role Signal Pathway Signal Transduction Spinal cord injury Staging Structure Sympathetic Ganglia Sympathetic Nervous System Synapses Synaptic plasticity Testing Therapeutic Tissues Translating Variant axon growth cognitive function developmental neurobiology extracellular in vitro Assay in vivo insight nerve supply nervous system development nervous system disorder neurodevelopment neuron development neuronal cell body neuronal survival neurotrophic factor novel programs receptor regenerative repaired research study response synaptogenesis trafficking

项目摘要

DESCRIPTION (provided by applicant): A fundamental question in developmental neurobiology is how a limited number of growth factors coordinate the establishment of precise neuronal circuits during nervous system development. Neurotrophins provide one of the best examples of target-derived developmental cues regulating neuronal survival, axonal and dendritic growth and synaptogenesis. An intriguing question in neurotrophin research is how a very large number of biological events are triggered by such a limited set of neurotrophins and their receptors. We previously reported that two different neurotrophins, Nerve Growth Factor (NGF) and Neurotrophin-3 (NT-3), employ the same TrkA receptor to promote sequential stages of axonal growth during sympathetic nervous system development. NT-3, secreted from the vasculature along the trajectory of projecting sympathetic axons, promotes early axon outgrowth. However, NGF derived from peripheral targets is required for final innervation of end- organs. How does a common TrkA receptor respond to two different neurotrophins to facilitate distinct phases of axon growth? We identified a calcineurin-dependent TrkA endocytic pathway that is critical for NGF-, but not NT-3-dependent trophic functions. Calcineurin is a calcium-responsive phosphatase that influences diverse aspects of neuronal development by translating small changes in intracellular calcium levels to morphological and transcriptional changes. Thus, the overall goal of this proposal is to test the hypothesis that the two neurotrophins, NGF and NT-3, differentially regulate TrkA signaling and trafficking to promote distinct stages of sympathetic axon growth. To this end, we will employ biochemical assays to identify TrkA signaling pathways that allow target-derived NGF and NT-3 to differentially activate calcineurin in sympathetic neurons. Using mutant mice lacking calcineurin or its downstream target, the endocytic GTPase, dynamin1, we will test the hypothesis that endocytosis of TrkA receptors is specifically required for NGF, but not NT-3-mediated sympathetic axonal growth in vivo. We will also define the mechanisms by which TrkA endocytosis promotes axonal growth. Together, these studies will provide novel insights into how two target-derived neurotrophins signal via a common TrkA receptor to cooperatively regulate axonal growth during neuronal development, as well as provide the foundation for addressing the role of these axonal growth programs in mediating regenerative growth of adult neurons following injury or disease.

描述（由申请人提供）：发育神经生物学中的一个基本问题是，在神经系统发育过程中，有限数量的生长因子如何协调确切的神经元回路的建立。神经营养蛋白提供了调节神经元存活，轴突和树突生长和突触发生的目标衍生发展线索的最佳例子之一。神经营养蛋白研究中的一个有趣的问题是，这组有限的神经营养蛋白及其受体如何触发大量的生物事件。我们先前报道说，两个不同的神经营养蛋白神经生长因子（NGF）和神经营养蛋白3（NT-3）采用相同的TRKA受体来促进交感神经系统发育过程中轴突生长的顺序阶段。 NT-3沿着投射交感轴突的轨迹分泌的NT-3促进了早期的轴突生长。但是，源自末端器官的最终神经支配需要源自外围靶标的NGF。常见的TRKA受体如何对两种不同的神经营养蛋白响应以促进轴突生长的不同阶段？我们确定了钙调蛋白依赖性的TRKA内吞途径，该途径对于NGF-至关重要，但不是NT-3依赖性的营养功能。钙调蛋白是一种钙响应性磷酸酶，通过将细胞内钙水平的小变化转化为形态学和转录变化，从而影响神经元发育的各个方面。因此，该提案的总体目标是检验以下假设：两个神经营养蛋白NGF和NT-3差异地调节TRKA信号传导和运输以促进交感神经轴突生长的不同阶段。为此，我们将采用生化测定来识别允许目标衍生的NGF和NT-3在交感神经元中差异激活钙调神经蛋白的TRKA信号通路。使用缺乏钙调蛋白或其下游靶标的突变小鼠，内吞GTPase dynamin1，我们将测试NGF的内吞作用，即NGF的内吞作用是特异性的，但不是NT-3-3介导的交感神经辅助轴突生长。我们还将定义TRKA内吞作用促进轴突生长的机制。总之，这些研究将提供新的见解，以了解如何通过常见的TRKA受体信号信号，以在神经元发育过程中调节轴突生长，并为解决这些轴突生长程序在介导成人神经元的再生生长中的作用的基础。