Fibrin-neutrophil interaction in periodontitis immunopathology

粘液免疫反应是调节口腔组织稳态的关键，但当被破坏时， 疾病。尽管对这一一般概念的认识已经确立，但口腔粘膜炎的具体机制仍有待进一步研究。 免疫力尚未完全了解。孟德尔疾病有助于理解口腔 通过揭示与人体免疫和粘膜稳态有关的基因和途径， 一种与口腔粘膜疾病明显相关的孟德尔疾病是纤溶酶原（Plg）缺乏症。Plg，是 纤溶酶是活性蛋白酶纤溶酶的前体，纤溶酶是血管内和 血管外间隙人Plg基因（PLG）中的纯合或复合杂合突变通常 导致严重的口腔粘膜疾病，这表明这种蛋白酶在粘膜免疫中的关键作用。的确， 这些患者表现为粘膜部位的纤维蛋白沉积和口腔粘膜疾病（木质牙周炎）。 在木质牙周炎中，纤维蛋白的过度沉积被假设为导致严重的软组织和牙槽骨损伤。 骨质破坏，并经常导致青春期整个牙列的缺失。然而，机械 粘膜纤维蛋白沉积和免疫病理学之间的联系尚不清楚。粘膜炎症和 牙列周围区域的纤维蛋白沉积和下层骨的破坏也是 常见的牙周炎根据大量的初步数据，席尔瓦博士制定了一个中央 假设粘膜纤维蛋白沉积通过局部接合促进牙周炎进展， 浸润性中性粒细胞的活化。为了验证这一假设，席尔瓦博士将追求三个具体目标：（1）确定 纤维蛋白溶解正常和受损条件下嗜酸性粒细胞-纤维蛋白结合在牙周骨丢失中作用 （2）确定纤维蛋白-中性粒细胞接合对于诱导中性粒细胞效应因子的贡献。 体外功能;和（3）药理学靶向纤维蛋白-中性粒细胞效应子功能以预防牙周炎 骨质流失这项研究的指导阶段将在席尔瓦博士的主要实验室进行。 导师，Moutsopoulos博士和Bugge在NIDCR，其中有所有必要的设备和设施，此外， 为牙周和纤维蛋白溶解研究提供了一个良好的智力环境。用于科研培训 为了帮助她的职业发展，席尔瓦博士组建了一个强大的咨询委员会， 纤维蛋白生物学、免疫学和中性粒细胞生物学知识。她还召集了一位专家顾问 她的团队帮助她发展新的研究技能，包括活细胞成像和基于计算机的图像分析。在 此外，席尔瓦博士将参加研讨会，讲习班和课程提供的NIH，以提高她的科学 沟通、赠款撰写、指导和领导技能。本研究沿着专项训练 活动，将产生出版物和初步数据，以帮助席尔瓦博士实现她的职业目标，成为 口腔健康和疾病领域的独立研究员。

Mucosal immune responses are key for the regulation of oral tissue homeostasis, but when disrupted will lead to disease. Despite well-established appreciation of this general concept, specific mechanisms of oral mucosal immunity are not yet completely understood. Mendelian diseases have been instrumental in understanding oral health and disease by uncovering genes and pathways implicated in human immunity and mucosal homeostasis. One Mendelian disease clearly linked to oral mucosal disease is Plasminogen (Plg) deficiency. Plg, is the precursor of the active protease plasmin, which is the primary fibrinolytic enzyme in both intravascular and extravascular space. Homozygous or compound heterozygous mutations in the human Plg gene (PLG) typically lead to severe oral mucosal disease, suggesting a critical role for this protease in mucosal immunity. Indeed, these patients present with fibrin deposition at mucosal sites and oral mucosal disease (ligneous periodontitis). In ligneous periodontitis, excessive deposition of fibrin is hypothesized to lead to severe soft tissue and alveolar bone destruction, and often results in the loss of the entire dentition in adolescence. However, the mechanistic link between mucosal fibrin deposition and immunopathology is not yet understood. Mucosal inflammation and fibrin deposition in areas surrounding the dentition and destruction of underlying bone are also the hallmarks of the common form of periodontitis. Based on extensive preliminary data, Dr. Silva has formulated a central hypothesis that mucosal fibrin deposition promotes periodontitis progression through the local engagement and activation of infiltrating neutrophils. To test this hypothesis, Dr. Silva will pursue three specific aims: (1) Determine the role of neutrophil-fibrin engagement in periodontal bone loss under compromised and normal fibrinolytic conditions; (2) Determine the contribution of fibrin-neutrophil engagement for the induction of neutrophil effector functions in vitro; and (3) Pharmacologically target fibrin-neutrophil effector functions to prevent periodontitis bone loss. The mentored phase of this research will be conducted in the laboratories of Dr. Silva’s primary mentors, Drs. Moutsopoulos and Bugge at NIDCR, which have all required equipment and facilities in addition to an excellent intellectual environment for periodontal and fibrinolysis research. For scientific research training and to help with her career growth, Dr. Silva has assembled a strong advisory committee to enhance her knowledge in fibrin biology, immunology and neutrophil biology. She has also assembled an expert consultant team to help her develop new research skills including live cell imaging and computer-based image analysis. In addition, Dr. Silva will attend seminars, workshops and courses provided at NIH to improve her scientific communication, grant writing, mentoring and leadership skills. This research, along with specific training activities, will generate publications and preliminary data to help Dr. Silva to achieve her career goal of becoming an independent researcher in the field of oral health and disease.