HYPOPHYSIOTROPIC NEURON DIFFERENTIATION--TARGET FEEDBACK

垂体神经元分化--目标反馈

• 批准号: 2891723
• 负责人: CAROL J PHELPS
• 金额: $ 20.11万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-12-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2891723
• 关键词: animal genetic material tag; apoptosis; developmental genetics; developmental neurobiology; dwarfism; gene induction /repression; gene mutation; growth factor receptors; hormone receptor; hormone regulation /control mechanism; hypothalamic pituitary axis; immunocytochemistry; insulinlike growth factor; laboratory mouse; neurogenesis; neurogenetics; neurons; neuropharmacology; neurotrophic factors; prolactin; receptor expression; somatotropin; transcription factor

DESCRIPTION: The proposed studies are designed to test the hypothesis that anterior pituitary hormones act as developmental neurotrophic signals for hypothalamic pituitary-regulating (hypophysiotropic) neurons. The broad, long-term objective of the research is to elucidate the mechanisms by which these endocrine signals affect hypophysiotropic neuron survival, differentiation, and axon terminal guidance. The studies will be conducted using two types of dwarf mouse with spontaneous pituitary transcription factor mutations that result in failure to produce growth hormone (GH) and prolactin (PRL), and which show concomitant abnormalities in neurons that produce GH-regulating somatostatin and GH-releasing hormone, and PRL-inhibiting DA. Thus, the effect of absent signal during development may be assessed without experimentation, and hormone treatments may be selective and specific. The general experimental design is evaluation of developmental events in the absence of target feedback, and of effects of hormone replacement on these events. The specific aims are to determine, in naive and hormone-treated dwarf mice, 1) the extent to which hypophysiotropic axons terminate aberrantly outside of or within the hypothalamic median eminence (ME) and whether this pattern is regressive, using anterograde and retrograde tract tracing, immunocytochemistry (ICC) and electron microscopy (EM), including assessment of axonal guidance molecules and structural elements in ME, 2) whether programmed cell death occurs postnatally among hypophysiotropic DA neurons, by ICC of apoptotic gene products, nucleosome end-labeling in situ, and EM, and 3) whether IGF-I and GDNF are respective mediators of GH and PRL effects, by assessing expression of these factors and their receptors using in situ hybridization and testing whether either factor can substitute for hormone replacement. Related to the assessment of mediators is Specific Aim 4, further examination of pathways and mechanisms of GH and PRL effect, by localizing GH and PRL receptors, identifying the JAK/STAT proteins that these receptors activate, measuring the expression of immediate-early gene products after GH or PRL treatment, and identifying the neuronal phenotypes showing receptor or activation, because hypophysiotropic neuron stimulation may be indirect.

描述：拟议的研究旨在检验以下假设。 前垂体激素充当发育性神经营养信号 下丘脑垂体调节（低生理）神经元。 广泛， 该研究的长期目标是阐明该机制 这些内分泌信号会影响下生理神经元的生存， 分化和轴突终端引导。 研究将进行 使用两种类型的矮人用自发性垂体转录 导致未能产生生长激素（GH）和的因子突变 催乳素（PRL），并且在神经元中表现出异常 产生GH调节的生长抑素和富含GH的激素，以及 抑制PRL DA。 因此，开发过程中缺乏信号的影响可能 在没有试验的情况下进行评估，激素治疗可能是选择性的 和具体。 一般的实验设计是评估 在没有目标反馈的情况下发展事件， 这些事件的激素替代。 具体目的是确定 天真和激素治疗的矮人小鼠，1） 下型轴突在外面或内部异常终止 下丘脑中位数杰出（我）以及这种模式是否回归， 使用顺行和逆行图，免疫细胞化学（ICC） 和电子显微镜（EM），包括评估轴突引导 我中的分子和结构元素，2）编程细胞死亡是否 由凋亡的ICC产后出现在下生理的DA神经元中 基因产物，原位核小体终端标记和EM，以及3）IGF-i是否是否 通过评估，GDNF是GH和PRL效应的各自的介体 使用原位杂交表达这些因素及其受体 并测试任何一个因素是否可以代替激素替代品。 与调解人评估有关的是特定目的4，进一步 通过本地化检查GH和PRL效应的途径和机制 GH和PRL受体，识别这些受体的JAK/STAT蛋白 激活，测量GH后立即进行早期基因产物的表达 或PRL处理，并鉴定出显示受体的神经元表型 或激活，因为低生理神经元刺激可能是间接的。