Regulation of Peptide Expression in Neuronal Cells

神经元细胞中肽表达的调节

• 批准号: 6636853
• 负责人: VICTOR MAY
• 金额: $ 30.68万
• 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/6636853
• 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、神经发育和神经发育的细胞机制 神经再生是一个复杂的过程，它平衡了神经元的存活和 增殖与分化。这些过程涉及到空间和 一系列神经调节因子的时间协调和 一种特殊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和 再生计划。许多神经肽能系统是 在神经肽家族中，血管活性肠肽 (VIP)/垂体腺苷环化酶激活多肽(PACAP)具有良好的 确立在神经递质和神经营养信号中的作用。 在我们对神经元递质和生物活性多肽产生的研究中，我们 鉴定PACAP多肽的高效刺激作用 颈上神经节交感神经元递质/肽 生产和分泌，建立了唯一的优先高效表达 选择性PACAP-PAC1(短)HOP1受体剪接变异体在SCG神经元和 证实了PAC1(简称)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/PAC1受体细胞机制的结构研究 因此，我们假设PAC1的能力 受体激活多个第二信使通路是其基础 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。我们的工作已经让人联想到小说 PACAP介导的PAC1受体Trp通道激活机制 神经传递素；我们将继续进行这些和补充研究与 PAC1受体激活特异性MEK/ERK和P13K/AM的营养作用 精确发育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的细胞内信号机制 受体介导的神经营养信号；2)定义特定的PAC1 受体介导的信号通路参与每一种神经营养反应； 3)明确TM通道在PACAP功能中的作用。我们感觉到了这些 研究不仅在了解PACAP/PAC1受体的作用方面是独一无二的 生理背景，但也是提供基本见解的重要信息 G蛋白偶联受体信号在神经功能中的不同作用 和发展。这些研究可能会为未来的战略提供建议，以促进 损伤和疾病的神经元再生。