Trigeminal Afferents Regulation of Apical Periodontitis Development

三叉神经传入对根尖牙周炎发展的调节

• 批准号: 10208856
• 负责人: Anibal Diogenes
• 金额: $ 36.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208856
• 关键词: Ablation; Address; Affect; Afferent Neurons; Alkaline Phosphatase; Amyloid beta-Protein; Biochemical; Biological; Biological Assay; Bone Pain; Bone Resorption; Bone remodeling; C Fiber; Capsaicin; Cell Communication; Cell Line; Cells; Chemicals; Clinical; Coculture Techniques; Data; Dental; Development; Disease; Fiber; Flow Cytometry; Genetic; Goals; High Pressure Liquid Chromatography; Human; Immune response; Immunohistochemistry; Infection; Inflammation Mediators; Investigation; Ion Channel; Knowledge; Lesion; Life; Lipids; Literature; Measures; Mediating; Microcomputers; Microscopy; Minerals; Mus; Neuroglia; Neurons; Neuropeptides; Nociceptors; Osteoblasts; Osteoclasts; PF4 Gene; Pain; Pathogenesis; Pathologic; Pathologic Processes; Pathway interactions; Patients; Periapical Periodontitis; Pharmaceutical Preparations; Process; Protein Array; Proteins; Proteomics; Quality of life; Quantitative Reverse Transcriptase PCR; Receptor Signaling; Regulation; Research; Role; Sensory; Signal Pathway; Skeletal system; Spectrophotometry; Stains; Structure; Structure of trigeminal ganglion; Testing; Therapeutic; Time; Tissues; Tooth Loss; Transgenic Mice; Trigeminal System; United States; attenuation; base; bone loss; clinically significant; craniofacial; density; dental infection; design; experimental study; gel electrophoresis; global health; immune function; immunoreactivity; in silico; in vivo; innovation; insight; lipidomics; mouse model; nerve supply; novel; novel strategies; novel therapeutics; oral condition; osteoblast differentiation; precursor cell; premature; receptor; release factor; response; screening; targeted treatment; tomography

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.

项目摘要 根尖周炎(Ap)是一种高度流行和使人衰弱的病理状态，其特点是 牙齿感染引起的骨吸收和疼痛。许多优雅的研究揭示了 免疫细胞和炎症介质在AP中的作用。尽管美联社人口密集 由三叉神经节(TG)纤维支配的神经传入在本病中的作用 这一过程在很大程度上是未知的。我们的初步数据表明，三叉神经节神经元调节AP 病变发展。这项建议的目的是了解TG纤维如何控制AP 发展，这在知识方面仍然是一个很大的差距。我们第一次提议， 研究神经元/非神经元细胞相互作用在控制AP发展中的作用 TG神经元的主要亚类。这是一种新颖且极其重要的策略。 感觉神经元对AP发育调控的研究 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有可能 差异很大；甚至对破骨细胞和成骨细胞产生相反的影响。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 由三叉神经节神经元发育。我们的中心假设是，在对感染的反应中， 亚类TG传入抑制根尖周炎的骨吸收 破骨和成骨活动。这一假设将在以下方面得到检验：目标1检验作用 不同亚类TG传入抑制骨吸收及免疫学作用的比较 感染诱导的AP小鼠模型的反应；目标2定义不同的参与 三叉神经节神经元亚类对破骨细胞和成骨细胞功能的调节；以及目标3 三叉神经节神经元不同亚类释放的可溶性因子(S)的确定与鉴定 以及它们对调节破骨细胞和成骨细胞功能的贡献。我们相信 这一应用程序产生的知识将从这两个方面产生实质性的积极影响 科学和临床的观点。从科学上讲，这是 利用亚类特异性TG小鼠株系研究AP。此外，生成的新的 深入了解神经元和树突状细胞重塑之间的相互作用将为进一步 科学进步。在临床上，神经调节机制的识别可以提供 新的战略，重要的是，开发抗AP疗法的目标。