Regulation of Peptide Expression in Neuronal Cells

描述（由申请人提供）： 神经发生、神经发育和神经再生的细胞机制 神经再生是平衡神经元存活和 增殖与分化。这些过程涉及空间和 一系列神经调节因子的时间编排， 特定的神经营养信号可以适应不同的 信号通路似乎是成功的神经元发育的关键， 再生计划许多神经肽能系统都是 在神经肽家族中，血管活性肠肽 (VIP)/垂体腺苷酸环化酶激活多肽（PACAP）具有良好的 在神经递质和神经营养信号传导中的作用。 在我们对神经递质和生物活性肽生产的研究中， 鉴定了PACAP肽在刺激免疫应答中的高效力和功效。 颈上级神经节交感神经递质/肽 生产和分泌，建立了只有 SCG神经元中PACAP选择性PAC1（短）HOP1受体剪接变体， 证明了PAC1（短）HOP1受体亚型与 多个细胞内信号级联。这些研究使我们能够 PACAP/PAC 1受体的细胞机制 功能;因此，我们假设PAC 1的能力 受体激活多种第二信使途径的基础， 在调节PACAP介导的许多不同方面的功能多样性 神经递质和神经营养作用。我们的工作已经表明， PACAP介导的PAC1受体Trp通道激活机制 神经传递;我们将继续这些和补充研究与 假设PAC 1受体激活特异性MEK/ERK和P13 K/AM营养 在精确的发育时期或改变的信号通路 生理状态，为神经元增殖提供关键信号， 分化或再生。我们的目标是：1）建立 PACAP/PAC 1的细胞内信号传导机制 受体介导的神经营养信号; 2）定义特定的PAC 1 受体介导的信号通路，参与每种神经营养反应; （3）确立Tm通道在PACAP功能中的作用。我们觉得这些 这些研究不仅在了解PACAP/PAC 1受体的作用， 生理背景，但也重要的IR提供必要的见解， G蛋白偶联受体信号在神经元功能中的不同作用 发展先行者的要求这些研究可能会建议未来的战略，以促进 神经元再生损伤和疾病。

DESCRIPTION (Provided by applicant): The cellular mechanisms underlying neurogenesis, neurodevelopment and neuroregeneration are complex processes hat balance neuronal survival and proliferation with differentiation. These processes involve the spatial and temporal orchestration of a succession of neuroregulatory factors and the facility with which particular neurotrophic signals can adapt to diverse signaling pathways appears key to a successful neuronal developmental and regeneration program. Many neuropeptidergic systems are essential components of that process and among neuropeptide families, the vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase activating polypeptides (PACAP) have well establishec roles in neurotransmitter and neurotrophic signaling. In our studies of neuronal transmitter and bioactive peptide production, we identified the high potency and efficacy of PACAP peptides in stimulating superior cervical ganglior SCG) sympathetic neuron transmitter/peptide production and secretion, established the preferential high expressior of only the PACAP-selective PAC1(short)HOP1 receptor splice variant in SCG neurons and demonstrated the unique coupling of PAC1 (short)HOP1 receptor isoform to multiple intracellular signaling cascades. These studies have allowed us to structure studies to define the cellular mechanisms of PACAP/PAC1 receptor function; accordingly, we have hypothesized that the ability for the PAC1 receptor to activate multiple second messenger pathways underlies its functional diversity in regulating the many different facets of PACAP-mediated neurotransmitter and neurotrophic actions. Our work has already suggested novel mechanisms of PAC1 receptor Trp channel activation in PACAP mediated neurotransmissin; we will pursue these and complementary studies with the postulate that PAC1 receptor activation of specific MEK/ERK and P13K/AM trophic signaling pathways during precise developmental periods or altered physiological states, provides critical signals for neuronal proliferation, differentiation or regeneration. Our aims are: 1) to establish the intracellular signaling mechanisms that transduce the PACAP/PAC1 receptor-mediated neurotrophic signals; 2) define the particular PAC1 receptor-mediated signaling pathway that engages each neurotrophic response; and 3) establish the roles of Tm channels in PACAP function. We feel these studies are unique not only in understanding PACAP/PAC1 receptor actions in physiological context, but also important ir providing essential insights to the diverse roles of G-protein coupled receptor signaling in neuronal function and development. These studies may suggest future strategies to facilitate neuronal regeneration to injury and disease.