NEUROTROPHIC FACTORS AND TRIGEMINAL PATTERN FORMATION

神经营养因子和三叉神经模式的形成

• 批准号: 6112161
• 负责人: MARK F JACQUIN
• 金额: $ 10.3万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112161
• 关键词: apoptosis; brain mapping; brain stem; developmental neurobiology; embryo /fetus; ganglions; gene expression; growth factor receptors; histochemistry /cytochemistry; in situ hybridization; intercellular connection; laboratory rat; neurogenesis; neuronal transport; neurotrophic factors; receptor binding; slow release drug; somesthetic sensory cortex; thalamus; trigeminal nerve

Our long-term goal is to reveal processes responsible for somatotopic pattern formation. Lesion, deprivation and descriptive paradigms have implicated ordered peripheral connections in the development of somatotopy; yet, impulse blockade has no effect on pattern formation. Thus, it is unclear what signalling mechanism is used by the periphery in establishing CNS patterns. We will employ the rodent whisker/barrel model to address the following general hypothesis: Somatotopic patterns result as a consequence of neurotrophically regulated, naturally occurring cell death in the trigeminal (V) ganglion. Preliminary data suggest novel causal relationships between nerve growth factor (NGF) level, V ganglion cell number, and the development of barrels, suggesting that regressive processes produce somatotopic patterns. To assess the validity and implications of these observations, and to begin to explore how neurotrophic factors impact on ganglion cell survival and CNS pattern formation, the following specific hypotheses will be tested in rats: 1: Whisker-related patterns emerge in fetal V brainstem nuclei during a period when large numbers of V ganglion cells die of natural causes. We will use an array of histochemical markers and image analysis to assay the development of whisker-related patterns, as well as stereological methods to determine if ganglion cell number predicts the emergence and relative maturity of somatotopic patterns. 2: V ganglion cells express mRNA message for different neurotrophic receptors during different phases of fetal development. In situ hybridization experiments will be carried out on fetal V ganglia to determine patterns of expression of the protein product of the trk proto-oncogene which has similar properties to the NGF high-affinity receptor, the trk-B gene product that binds brain-derived neurotrophic factor (BDNF), and the trk-C gene product that binds neurotrophin-3 (NT-3). A retrograde tracer will also be used to correlate projection status with receptor gene expression over the period of naturally occurring ganglion cell death and CNS pattern formation. 3: systemic delivery of NGF, BDNF and/or NT-3 will rescue V ganglion cells from naturally occurring cell death. We will determine the ages at which each or all of these neurotrophic factors is most effective in sustaining supernumerary V ganglion cells. A slow-release, chronic delivery procedure will be used for convenient, long-term delivery of NGF, BDNF, and/or NT-3 at varying fetal ages. 4: Central V patterns do not develop when supernumerary V ganglion cells are sustained by neurotrophic augmentation. Histochemical markers, image analysis, and ganglion cell stereology will be used in each animal to reveal relationships between ganglion cell number and whisker-related patterns in the brainstem, thalamus, and barrel cortex. Postnatal cases will also be studied to determine if ganglion cells are permanently rescued and if pattern formation is permanently interrupted. These studied may uncover general principles controlling somatosensory development in humans in light of recent indications that humans have somatotopically parcellated, barrel-like aggregations in V and dorsal column nuclei. Biological actions of neurotrophic factors will also be revealed that may be of clinical value.

我们的长期目标是揭示负责体位反应的过程 图案形成。 损害、剥夺和描述范式已经 在发展过程中涉及有序的外围连接 躯体发育；然而，冲动封锁对形态形成没有影响。 因此，尚不清楚外围设备使用什么信号机制 建立 CNS 模式。 我们将使用啮齿动物的胡须/桶 模型来解决以下一般假设：体位模式 自然地，神经营养调节的结果 三叉神经节中发生细胞死亡。 初步数据 提出神经生长因子（NGF）之间新的因果关系 水平、V 神经节细胞数量和桶状发育，表明 回归过程产生体位模式。 评估 这些观察的有效性和影响，并开始探索 神经营养因子如何影响神经节细胞存活和中枢神经系统模式 形成，将在大鼠中测试以下具体假设：1： 胎儿 V 脑干核中出现晶须相关模式 大量 V 神经节细胞因自然原因死亡的时期。 我们 将使用一系列组织化学标记和图像分析来进行分析 与晶须相关的图案以及体视学的发展 确定神经节细胞数量是否预示出现的方法 体位模式的相对成熟度。 2：V神经节细胞表达 不同阶段不同神经营养受体的 mRNA 信息 胎儿发育的情况。 将进行原位杂交实验 在胎儿 V 神经节上确定蛋白质的表达模式 trk原癌基因的产物，与NGF具有相似的特性 高亲和力受体，trk-B 基因产物，结合脑源性 神经营养因子 (BDNF) 以及结合的 trk-C 基因产物 神经营养素-3 (NT-3)。 逆行示踪剂也将用于 将一段时间内的投射状态与受体基因表达相关联 自然发生的神经节细胞死亡和中枢神经系统模式形成。 3：全身递送 NGF、BDNF 和/或 NT-3 将挽救 V 神经节 细胞自然发生的细胞死亡。 我们将确定年龄 其中每一个或所有这些神经营养因子最有效 维持多余的V神经节细胞。 缓慢释放、慢性 交付程序将用于方便、长期的交付 不同胎儿年龄的 NGF、BDNF 和/或 NT-3。 4：中央V纹做 当多余的 V 神经节细胞由 神经营养增强。 组织化学标记、图像分析和 神经节细胞体视学将用于每只动物来揭示 神经节细胞数量与胡须相关模式之间的关系 位于脑干、丘脑和桶状皮层。 产后病例也会 进行研究以确定神经节细胞是否被永久拯救以及是否 图案形成永久中断。 这些研究可能会揭示 控制人类体感发育的一般原则 鉴于最近的迹象表明人类已经进行了体细胞分区， V 核和背柱核中的桶状聚集。 生物 神经营养因子的作用也将被揭示，这可能是 临床价值。