VIP AND PACP ACTION IN CNS DEVELOPMENT AND INJURY

血管活性肠肽(VIP)及其相关神经肽 脑下垂体腺苷环化酶激活肽(PACAP)是有效的 神经母细胞增殖和存活的体外调节。 给怀孕小鼠注射血管活性肠肽拮抗剂后， 子代小头畸形情况，为人类提供了一种新的模型 几乎总是与精神发育迟滞有关的疾病。在……里面 此外，已发现VIP在神经损伤中高度上调。 模型，PACAP已被发现可以降低细胞死亡的程度 实验性前脑缺血后的海马体。因此， VIP/PACAP配体/受体系统在中枢神经系统形态发生中的重要作用 和受伤。关于发展，目前的模式认为 VIP是从母亲胎盘衍生而来的，因此起到了 胚胎中枢神经系统生长的全球调节者。然而，来自这一点的关键数据 实验室研究表明，vip基因在小鼠体内表达。 后脑早在胚胎第11天，表明这些多肽是 源自胚胎，并在本地(而不是全球)发挥作用 调节中枢神经系统的发育。 在该方案中，VIP的时间和空间表达模式 和PACAP及其受体在正常发育过程中 采用原位杂交和免疫组织化学方法进行检测。这个 潜在靶细胞类型的表型将通过以下方式确定 用不同发育神经的标志物共同定位受体 血统。还将确定VIP/PACAP配体/受体是否 在损伤模型中，系统被上调。基于以下模式 多肽和受体在发育过程和损伤后的表达， 将建立体外模型来研究生长-或损伤- 这些多肽对相关细胞群信号的相关作用 导致这些动作的转导通路将被用来研究 药理学、生化学、分子生物学方法。结果是 预计将提供重要的机械性信息，说明 VIP、PACAP等多肽与中枢神经系统发育正常和异常 在发育中的大脑受到损伤后。

Vasoactive intestinal peptide (VIP) and the related neuropeptide pituitary adenylate cyclase activating peptide (PACAP) are potent regulators of neuroblast proliferation and survival in vitro. Administration of a VIP antagonist to pregnant mice produced a microcephaly condition in offspring, providing a new model for a human disease that is nearly always associated with mental retardation. In addition, VIP has been found to be highly upregulated in nerve injury models, and PACAP has been found to reduce the degree of cell death in the hippocampus following experimental forebrain ischemia. Thus, the VIP/PACAP ligand/receptor system may be important in CNS morphogenesis and injury. With respect to development, the current model contends that VIP is derived transplacentally from the mother, and thereby acts as a global regulator of embryonic CNS growth. However, key data from this laboratory indicate that the VIP gene is expressed in the mouse hindbrain as early as embryonic day 11, suggesting that the peptides are derived from the embryo and act in local domains (rather than globally) to regulate CNS development. In this proposal, the temporal and spatial expression patterns of VIP and PACAP, and their receptors during normal development will be determined using in situ hybridization and immunohistochemistry. The phenotype of potential target cell types will be identified by colocalizing receptors with markers for various developing neural lineages. It will also be determined if the VIP/PACAP ligand/receptor system is upregulated in an injury model. Based on the patterns of expression of peptide and receptor during development and after injury, in vitro model will be established to study the growth- or injury- related actions of these peptides on relevant cell populations Signal transduction pathways leading to these actions will be examined using pharmacological, biochemical, an molecular approaches. The results are expected to provide important mechanistic information on the role of peptides such as VIP and PACAP in normal and abnormal CNS development and after injury to the developing brain.