Fibrin-neutrophil interaction in periodontitis immunopathology

粘膜免疫反应是调节口腔组织动态平衡的关键，但当被破坏时，将导致 为了疾病。尽管人们已经很好地理解了这一普遍概念，但口腔粘膜的具体机制 豁免权还没有完全被理解。孟德尔式的疾病有助于理解口腔 健康和疾病，通过发现与人类免疫和粘膜动态平衡有关的基因和途径。 孟德尔一种明显与口腔粘膜疾病有关的疾病是纤溶酶原(PLG)缺乏症。PLG，是不是 活性蛋白酶纤溶酶的前体，它是血管内和血管内的主要纤溶酶 血管外空间。人类PLG基因的纯合子或复合杂合性突变 导致严重的口腔粘膜疾病，这表明该酶在粘膜免疫中起着关键作用。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认为会导致严重的软组织和牙槽。 骨质破坏，通常会导致青春期整个牙列的丧失。然而，机械论 粘膜纤维蛋白沉积和免疫病理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底层骨的破坏也是牙列周围的特征 牙周炎的常见形式。基于广泛的初步数据，席尔瓦博士制定了一个中心 假设粘膜纤维蛋白沉积通过局部参与和促进牙周炎进展 浸润性中性粒细胞的激活。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 中性粒细胞-纤维蛋白结合在纤溶功能受损和正常状态下牙周骨丢失中的作用 (2)测定纤维蛋白-中性粒细胞结合在诱导中性粒细胞效应中的作用。 体外功能；(3)药理靶向纤维蛋白-中性粒细胞效应器功能预防牙周炎 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 NIDCR的导师，Moutsopoulos博士和Bugge博士，他们还拥有所有必要的设备和设施 为牙周和纤溶研究提供良好的智力环境。用于科研培训 为了帮助她的事业发展，席尔瓦博士组建了一个强大的顾问委员会来加强她的能力 具备纤维蛋白生物学、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 帮助她开发新的研究技能，包括活细胞成像和基于计算机的图像分析。在……里面 此外，席尔瓦博士将参加NIH提供的研讨会、研讨会和课程，以提高她的科学水平 沟通、助学金撰写、指导和领导技能。这项研究，以及具体的培训 活动，将产生出版物和初步数据，以帮助席尔瓦博士实现她成为 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.