Regulation of Peptide Expression in Neuronal Cells

神经元细胞中肽表达的调节

• 批准号: 6520871
• 负责人: VICTOR MAY
• 金额: $ 30.49万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520871
• 关键词: cyclic AMP; developmental neurobiology; gene expression; immunocytochemistry; inositol phosphates; mitogen activated protein kinase; neural plasticity; neuroendocrine system; neurogenesis; neuropeptide receptor; neuropeptides; neurotransmitter biosynthesis; neurotransmitter receptor; neurotrophic factors; phosphatidylinositol 3 kinase; receptor expression; second messengers; superior cervical ganglion; tissue /cell culture

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.

描述（由申请人提供）： 神经发生、神经发育和神经发生的细胞机制 神经再生是平衡神经元存活和恢复的复杂过程 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和 特定的神经营养信号可以适应不同的设施 信号通路似乎是神经元成功发育和发育的关键 再生计划。许多神经肽能系统是神经系统的重要组成部分 这个过程以及神经肽家族中的血管活性肠肽 (VIP)/垂体腺苷酸环化酶激活多肽(PACAP)具有良好的 建立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，我们 确定了 PACAP 肽在刺激方面的高效能和功效 颈上神经节SCG）交感神经递质/肽 产生和分泌，建立了唯一的优先高表达 SCG 神经元中的 PACAP 选择性 PAC1(short)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 结构研究以确定 PACAP/PAC1 受体的细胞机制 功能;因此，我们假设 PAC1 的能力 受体激活多个第二信使途径是其基础 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。我们的作品已经推荐了小说 PACAP介导的PAC1受体Trp通道激活机制 神经传递素；我们将与 假设 PAC1 受体激活特定的 MEK/ERK 和 P13K/AM 营养性 精确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 转导 PACAP/PAC1 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PAC1 参与每种神经营养反应的受体介导的信号通路； 3) 确定 Tm 通道在 PACAP 功能中的作用。我们感受到这些 研究的独特之处不仅在于了解 PACAP/PAC1 受体在 生理背景，但提供基本见解也很重要 G 蛋白偶联受体信号传导在神经元功能中的多种作用 和发展。这些研究可能会提出未来的策略，以促进 神经元再生以应对损伤和疾病。