IFI16 is a Periodontitis Modulating Protein

摘要 此申请表是为促进牙科、口腔和牙科专业的多样性而设立的导师职业发展奖。 朱莉·马切森博士的头面部研究人员(K01)。她正在进行一项关于 IFI16通过AIM2炎症体和细胞因子/趋化因子调节牙周组织破坏 表情。提出的实验的理论基础得到了文献和初步数据的支持 申请人。这一奖项将使Marchesan a)博士成为牙周炎和牙周炎的专家。 答复，b)培训机械方法的应用和解释，以提高质量 她目前从事的翻译研究，c)发展一项独立的研究事业， 允许她与临床和基础研究人员合作，以及d)增加拉丁裔的代表性 在学术界独立资助口腔健康研究的女性。一支多学科的团队 专家们已经同意在基于这项申请的资金的基础上在这项研究提案期间支持朱莉。这个 有理由将研究人员纳入本申请的团队和主要专业知识是：a)Steve博士 Offenbacher(牙周学翻译研究联合导师)，b)Jenny Ting博士(联合导师，主持人 答复)，c)Jennifer Webster-Cyriaque博士(支持小组，微生物-宿主互动)，John博士 Preisser(支持团队，生物统计学)和Andrea Azcarate-Peril博士(支持团队，特性 微生物种群)。这一机械性的建议与这些机构提供的指导相结合 成功的研究人员将为Marchesan博士成为一名成功的 独立的调查者和高度代表学术界的多样性。 牙周病影响了几乎一半的美国成年人，是牙齿脱落的主要原因。 可用于治疗牙周炎的药理药物的缺乏为研究提供了充分的理由 牙周炎的宿主反应和潜在的炎症调节因子。Marchesan博士的初步数据 证实IFI16在人牙周组织的多种细胞中表达，包括上皮细胞， 内皮细胞、成纤维细胞和炎性细胞的浸润性。她还表明，IFI16基因过度表达 减少趋化因子的反应。研究发现，在基因敲除动物中，这种蛋白质的缺乏显著 增加牙周骨丢失量加强了这种蛋白质调节的证据 发炎。提议的应用程序将利用机械性方法(过度表达，沉默， 基因敲除动物、骨髓移植、蛋白质抑制)，以研究IFI16作为一种调节因子的作用 牙周宿主反应。该项目将评估IFI16作为牙周宿主反应的调节剂 体外(SA1)；我们建议探索a)在体内阻碍炎症组织破坏的IFI16和b) 利用目前可用的治疗剂(SA2)；我们将确定IFI16的主要细胞来源 它负责炎症反应调节(SA3)。虽然目前还没有治疗方法 特别针对IFI16，有针对AIM2-炎症体产物的可用药物，例如 Caspase-1抑制剂。这些实验的长期目标是更好地理解 控制炎症对牙周组织的破坏。Marchesan博士的研究将为 了解炎症小体在牙周组织破坏中的调节并允许发生 探索炎症体和治疗牙周炎的潜在疗法的新未来项目将于#年底完成 这个为期5年的资助期。

ABSTRACT This application is for a Mentored Career Development Award to Promote Diversity in the Dental, Oral and Craniofacial Research Workforce (K01) for Dr. Julie Marchesan. She is conducting research into the role of IFI16 as a modulator of periodontal tissue destruction via AIM2 inflammasome and cytokine/chemokine expression. The rationale for the proposed experiments is supported by the literature and preliminary data of the applicant. This award will allow Dr. Marchesan a) to become an expert in periodontal inflammation and host response, b) to train in application and interpretation of mechanistic approaches in order to increase the quality of the translational research she currently conducts, c) to develop an independent research career that will allow her to collaborate with clinical and basic researchers, and d) to increase the representation of Latino women that are in academia and independently funded in oral health research. A multidisciplinary team of experts has agreed to support Julie during this research proposal based upon funding of this application. The team and main expertise that justified inclusion of the researcher in this application are: a) Dr. Steve Offenbacher (co-mentor, translational research in periodontology), b) Dr. Jenny Ting (co-mentor, host response), c) Dr. Jennifer Webster-Cyriaque (support team, microorganisms-host interactions), Dr. John Preisser (support team, biostatistics) and Dr. Andrea Azcarate-Peril (support team, characterization of microbial populations). The combination of this mechanistic proposal with the guidance afforded by these successful researchers will provide the necessary environment for Dr. Marchesan to become a successful, independent investigator and highly represent diversity in academia. Periodontal disease affects almost half of the American adult population and is a major cause of tooth loss. The paucity of pharmacologic agents available to treat periodontitis provides sufficient justification for studying the host response and potential inflammatory modulators of periodontitis. Dr. Marchesan's preliminary data demonstrate that IFI16 is expressed in multiple cells of human periodontal tissues, including epithelial, endothelial, fibroblasts and cells of the inflammatory infiltrate. She also showed that IFI16 overexpression decreases the chemokine response. The finding that the lack of this protein in knockout animals significantly increases the amount of periodontal bone loss strengthens the evidence that this protein modulates inflammation. The proposed application will utilize mechanistic approaches (overexpression, silencing, knockout animals, bone marrow-transplants, protein inhibition) to study the role of IFI16 as a modulator of the periodontal host response. This project will evaluate IFI16 as a modulator of the periodontal host response in vitro (SA1); we propose to explore a) IFI16 hindering inflammatory tissue destruction in vivo and b) the utilization of a currently available therapeutic agent (SA2); and we will identify the main cellular source of IFI16 that is responsible for inflammatory response modulation (SA3). While there are no current therapies specifically targeting IFI16, there are available drugs that target products of AIM2-inflammasome, such as caspase-1 inhibitors. The long-term goal of these experiments is to better understand modulation of inflammation to control periodontal tissue destruction. Dr. Marchesan's research will provide a basis for understanding inflammasome modulation in periodontal tissue destruction and allow the development of a novel future project exploring inflammasomes and potential therapies for treating periodontitis by the end of this 5-year funding period.