CGRP Regulation of iNOS and MAP Kinases/Phosphatases in Trigeminal Ganglia Glia

CGRP 对三叉神经节神经胶质细胞中 iNOS 和 MAP 激酶/磷酸酶的调节

• 批准号: 7152221
• 负责人: PAUL L DURHAM
• 金额: $ 24.36万
• 依托单位: MISSOURI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7152221
• 关键词: glia; inflammation; mitogen activated protein kinase; neurons; organ culture; pain; role

DESCRIPTION (provided by applicant): The long-term goals of the proposed studies are to understand the cellular/molecular mechanisms regulating neuronal-glial interactions during temporomandibular joint (TMJ) pathology and therapy. Neuronal-glial interactions play a key role during inflammation and pain yet the cellular mechanisms are not well understood. The proposed studies will focus on the roles of calcitonin gene-related peptide (CGRP), nitric oxide (NO), and mitogen-activated protein (MAP) kinases in initiating and maintaining TMJ inflammation. Elevated levels of the neuropeptide CGRP and multifunctional signaling molecule NO in synovial fluid of arthritic TMJs correlate with chronic inflammation and pain and contribute to TMJ degeneration. Recently, MAP kinases have been reported to be important in the underlying pathology of inflammatory diseases. We will test the hypothesis that neuronal release of CGRP activates trigeminal glial cells causing increases in secondary messengers and induction of specific MAP kinases and iNOS that stimulate production and release of NO. Importantly, we have shown that NO increases CGRP synthesis and release from trigeminal neurons. Thus, we will investigate the cellular mechanisms involved in neuronal-glial interactions that help to sustain a pathological inflammatory cycle central to chronic inflammation and pain associated with TMJ disorders (TMD). In addition, we will determine the role of MAP kinase phosphatases, which function to regulate MAP kinase activity and thus, reduce inflammation. To accomplish these goals, primary cultures of trigeminal ganglia and trigeminal ganglia organ cultures as well as in vivo studies in a model of TMJ inflammation will be utilized. Results from these studies will provide insight into the molecular mechanisms by which CGRP release from trigeminal neurons modulates iNOS gene expression in glial cells that is likely to facilitate identification of new molecular targets for treating TMD and other orofacial diseases. It is estimated that 11 million American adults now suffer from symptoms attributed to TMD. Since TMD predominantly affects women of childbearing age and can be associated with significant morbidity, these disorders have significant social and economic ramifications. In the search for new treatment modalities to treat acute inflammation and chronic pain, a thorough understanding of the signaling molecules and pathways involved in neuronal and glial cell activation within the trigeminal ganglion would be beneficial.

描述（由申请人提供）：拟议研究的长期目标是了解颞下颌关节（TMJ）病理学和治疗过程中调节神经元-胶质细胞相互作用的细胞/分子机制。神经元-胶质细胞相互作用在炎症和疼痛过程中发挥着关键作用，但其细胞机制尚不清楚。拟议的研究将重点关注降钙素基因相关肽（CGRP）、一氧化氮（NO）和丝裂原激活蛋白（MAP）激酶在引发和维持颞下颌关节炎症中的作用。关节炎 TMJ 滑液中神经肽 CGRP 和多功能信号分子 NO 水平升高与慢性炎症和疼痛相关，并导致 TMJ 变性。最近，据报道 MAP 激酶在炎症性疾病的潜在病理学中很重要。我们将检验以下假设：CGRP 的神经元释放会激活三叉神经胶质细胞，导致第二信使增加并诱导特定 MAP 激酶和 iNOS，从而刺激 NO 的产生和释放。重要的是，我们已经证明，NO 会增加三叉神经元 CGRP 的合成和释放。因此，我们将研究神经元-胶质细胞相互作用所涉及的细胞机制，这些相互作用有助于维持与颞下颌关节紊乱（TMD）相关的慢性炎症和疼痛的病理炎症循环。此外，我们将确定 MAP 激酶磷酸酶的作用，其功能是调节 MAP 激酶活性，从而减少炎症。为了实现这些目标，将利用三叉神经节和三叉神经节器官培养物的原代培养物以及颞下颌关节炎症模型的体内研究。这些研究的结果将深入了解三叉神经元释放的 CGRP 调节神经胶质细胞中 iNOS 基因表达的分子机制，这可能有助于识别治疗 TMD 和其他口面部疾病的新分子靶点。据估计，目前有 1100 万美国成年人患有 TMD 症状。由于 TMD 主要影响育龄妇女，并且可能与显着的发病率相关，因此这些疾病具有显着的社会和经济影响。在寻找治疗急性炎症和慢性疼痛的新治疗方法时，彻底了解三叉神经节内神经元和神经胶质细胞激活所涉及的信号分子和通路将是有益的。