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

描述（由申请人提供）：拟议研究的长期目标是了解在颞下颌关节（TMJ）病理和治疗过程中调节神经元-胶质相互作用的细胞/分子机制。神经元-神经胶质相互作用在炎症和疼痛中起着关键作用，但其细胞机制尚不清楚。拟开展的研究将重点关注降钙素基因相关肽（CGRP）、一氧化氮（NO）和丝裂原活化蛋白（MAP）激酶在启动和维持TMJ炎症中的作用。关节炎性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，并有助于TMJ退变。最近，MAP激酶被报道在炎症性疾病的基础病理中起重要作用。我们将验证CGRP的神经元释放激活三叉神经胶质细胞的假设，导致次级信使增加，并诱导特定MAP激酶和iNOS刺激NO的产生和释放。重要的是，我们已经证明NO增加三叉神经细胞的CGRP合成和释放。因此，我们将研究参与神经元-神经胶质相互作用的细胞机制，这些相互作用有助于维持与TMJ疾病（TMD）相关的慢性炎症和疼痛相关的病理性炎症循环。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，三叉神经节原代培养和三叉神经节器官培养以及TMJ炎症模型的体内研究将被利用。这些研究的结果将为三叉神经细胞释放CGRP调节神经胶质细胞中iNOS基因表达的分子机制提供深入的见解，这可能有助于识别治疗TMD和其他口腔面部疾病的新分子靶点。据估计，现在有1100万美国成年人患有由TMD引起的症状。由于TMD主要影响育龄妇女，并可能与显著发病率相关，因此这些疾病具有显著的社会和经济后果。在寻找治疗急性炎症和慢性疼痛的新治疗方式时，深入了解三叉神经节内神经元和胶质细胞活化的信号分子和途径将是有益的。

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.