VIP AND PACP ACTION IN CNS DEVELOPMENT AND INJURY

血管活性肠肽及其相关神经肽 垂体腺苷酸环化酶激活肽（PACAP） 体外成神经细胞增殖和存活的调节剂。 对妊娠小鼠给予VIP拮抗剂产生了一种 在后代的小头畸形状况，提供了一个新的模型，为人类 几乎总是与智力迟钝有关的疾病。在 此外，已经发现VIP在神经损伤中高度上调， 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。因此 VIP/PACAP配体/受体系统可能在中枢神经系统形态发生中起重要作用 和伤害。关于发展，目前的模式认为， VIP是从母亲经胎盘获得的，因此作为一种免疫调节剂。 胚胎中枢神经系统生长的全球调节器。然而，关键数据显示， 实验表明VIP基因在小鼠中表达， 早在胚胎第11天， 源自胚胎，并在局部领域（而不是全局）发挥作用 调节中枢神经系统的发育 在这个建议中，VIP的时空表达模式， 和PACAP，以及它们在正常发育过程中的受体， 使用原位杂交和免疫组织化学测定。的 潜在靶细胞类型的表型将通过 共定位受体与各种发育中的神经 血统还将确定VIP/PACAP配体/受体 系统在损伤模型中上调。根据这些模式 在发育过程中和损伤后肽和受体的表达， 将建立体外模型来研究生长-或损伤- 这些肽对相关细胞群的相关作用 导致这些作用的转导途径将使用 药理学、生物化学和分子生物学方法。结果 预计将提供重要的机制信息的作用， VIP和PACAP等肽在正常和异常CNS发育中的作用 以及发育中的大脑受伤后。

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.