Trigeminal Afferents Regulation of Apical Periodontitis Development

项目摘要 根尖牙周炎（AP）是一种高度流行和衰弱的病理条件，其特征是 牙齿感染导致的骨吸收和疼痛。许多优雅的研究表明， 免疫细胞和炎症介质在AP中的作用。尽管AP密集 由三叉神经节（TG）纤维支配，这些传入神经参与这种疾病 过程基本上是未知的。我们的初步数据表明，TG神经元调节AP 病变发展本提案的目的是了解TG纤维如何控制AP 发展，这仍然是一个巨大的知识差距。我们首次提议 研究神经元/非神经元细胞相互作用在控制AP发展中的四种 TG神经元的主要亚类。这是一个新颖的和至关重要的战略， 研究感觉神经元对AP发育的调节，因为每个神经元亚类 具有独特的功能和生化组成，包括独特的受体，离子通道 和神经肽。因此，TG神经元亚群的调节潜力可能 甚至对破骨细胞和成骨细胞产生相反的作用。所以 根据文献和初步实验，我们设计了一种新的学习AP的策略 TG神经元的发育。我们的中心假设是，在应对感染， TG传入神经亚类通过调节 成骨细胞和成骨细胞活性。这一假设将在以下方面得到检验： TG不同亚类传入纤维在抑制骨吸收和免疫反应中的作用 感染诱导的AP小鼠模型中的反应;目的2定义不同的参与 TG神经元亚类对骨形成和成骨细胞功能的调节;目的3 定义和鉴定从TG神经元的不同亚类释放的可溶性因子 以及它们对调节破骨细胞和成骨细胞功能的作用。我们认为 该应用程序所产生的知识将从以下两个方面产生实质性的积极影响 科学和临床观点。从科学上讲，这是一种主要的新颖方法， 使用亚类特异性TG小鼠系研究AP。此外，所产生的新 深入了解神经元和DCS重塑之间的相互作用将为进一步的研究开辟途径。 科学进步在临床上，神经元调节机制的鉴定可以提供 新的策略，更重要的是，开发抗AP疗法的靶点。

Project Summary Apical periodontitis (AP) is a highly prevalent and debilitating pathological condition marked by bone resorption and pain as result of dental infections. Many elegant studies have revealed the functions of immune cells and inflammatory mediators in AP. Despite AP being densely innervated by trigeminal ganglia (TG) fibers, the participation of these afferents in this disease process is largely unknown. Our preliminary data demonstrate that TG neurons regulate AP lesion development. The objective of this proposal is to understand how TG fibers control AP development, which remains a large gap in knowledge. We, for the first time, propose to investigate neurons/non-neuronal cell interaction in control of AP development for each of four major subclasses of TG neurons. This is novel and critically important strategy in approaching research on regulation of AP development by sensory neurons, since each neuronal sub-class has distinct function and biochemical make up, including unique sets of receptors, ion channels and neuropeptides. Hence, it is possible that regulatory potential of TG neuronal subsets could dramatically vary; and even produce opposite effects on osteoclasts and osteoblasts. So according to literature and preliminary experiments, we designed a novel strategy on study AP development by TG neurons. Our central hypothesis is that in response to infection certain subclasses of TG afferents inhibit bone resorption in apical periodontitis via the regulation of osteoclastic and osteoblastic activities. This hypothesis will be tested in: Aim 1 examining role of different subclasses of TG afferents in inhibiting bone resorption and immunological responses in a murine model of infection-induced AP; Aim 2 defining involvement of different subclasses of TG neurons on regulation of osteoclastic and osteoblastic functions; and Aim 3 defining and identifying the released soluble factor(s) from different subclasses of TG neurons and their contribution to modulation of osteoclast and osteoblast functions. We believe that knowledge generated by this application will have a substantial positive impact from both scientific and clinical perspectives. Scientifically, this is the principally novel approach in investigation of AP using subclass-specific TG mouse lines. Moreover, the generated new insight into interactions between neurons and DCS remodeling will open pathways for further scientific advancement. Clinically, identification of neuronal regulatory mechanisms could offer novel strategies and, importantly, targets for developing anti-AP therapeutics.