IFI16 is a Periodontitis Modulating Protein

IFI16 是一种牙周炎调节蛋白

• 批准号: 10225509
• 负责人: Julie Teresa Marchesan
• 金额: $ 13.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-10 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225509
• 关键词: Academia; Adult; Affect; Alveolar Bone Loss; American; Anti-Inflammatory Agents; Attenuated; Award; B-Lymphocytes; Binding; Biometry; Bone Marrow; Bone Marrow Transplantation; CASP1 gene; CD14 gene; CD3 Antigens; Cells; Chemotaxis; Clinical; Co-Immunoprecipitations; Data; Dental; Development; Disease; Drug Targeting; Endothelium; Environment; Epithelial; Equilibrium; Fibroblasts; Flow Cytometry; Fluorescence; Funding; Future; Gene Expression; Gene Proteins; Gingiva; Goals; Human; Immune; Immune response; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Innate Immune Response; Interferon Type II; Interleukin-1 beta; Interleukin-18; K-Series Research Career Programs; Latino; Ligature; Link; Literature; Maintenance; Manuscripts; Mass Spectrum Analysis; Mediating; Mentors; Modeling; Mus; Oral; Oral health; Osteoclasts; Pathogenesis; Periodontal Diseases; Periodontitis; Pharmacology; Population; Porphyromonas gingivalis; Protein Inhibition; Proteins; Publications; Research; Research Personnel; Research Proposals; Role; Sampling; Severities; Source; System; T-Lymphocyte; Techniques; Therapeutic Agents; Tissue Stains; Tissues; Tooth Loss; Training; Translational Research; Tumor-infiltrating immune cells; United States; Woman; alveolar bone; anti-CD20; base; bone; bone loss; career; cell type; chemokine; craniofacial; cytokine; experimental study; genetic manipulation; host-microbe interactions; in vivo; interleukin-1beta-converting enzyme inhibitor; knockout animal; macrophage; microCT; microbial; microorganism; multidisciplinary; neutrophil; novel; oral commensal; oral microbial community; osteoclastogenesis; overexpression; pathobiont; pathogen; periodontopathogen; public health relevance; response; sensor; training opportunity

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.

摘要 此应用程序是一个指导职业发展奖，以促进牙科，口腔和 Julie Marchesan博士的颅面研究工作队（K 01）。她正在研究 IFI 16通过AIM 2炎性体和细胞因子/趋化因子作为牙周组织破坏的调节剂 表情所提出的实验的基本原理得到了文献和初步数据的支持， 申请人。该奖项将使Marchesan博士a）成为牙周炎症和主机专家 响应，B）在机械方法的应用和解释方面进行培训，以提高质量 她目前进行的转化研究，c）发展独立的研究生涯， 允许她与临床和基础研究人员合作，以及d）增加拉丁美洲人的代表性 女性在学术界和独立资助的口腔健康研究。的多学科团队 专家已同意支持朱莉在此研究建议的基础上，本申请的资金。的 证明本申请中包含研究人员的团队和主要专业知识是：a）Steve博士 Offenbacher（共同导师，牙周病转化研究），B）Jenny Ting博士（共同导师，主持人 c）Jennifer Webster-Cyriaque博士（支持团队，微生物-宿主相互作用），John博士 Preisser（支持团队，生物统计学）和Andrea Azcarate-Peril博士（支持团队， 微生物种群）。这一机制性建议与这些建议提供的指导相结合， 成功的研究人员将为Marchesan博士成为一名成功的， 独立调查员和高度代表学术界的多样性。 牙周病影响几乎一半的美国成年人口，是牙齿脱落的主要原因。 治疗牙周炎的药物的缺乏为研究牙周炎提供了充分的理由。 牙周炎的宿主反应和潜在的炎症调节剂。马奇森博士的初步数据 证明了IFI 16在人牙周组织的多种细胞中表达，包括上皮细胞， 内皮细胞、成纤维细胞和炎性浸润细胞。她还表明，IFI 16过表达 降低趋化因子反应。这一发现表明，在基因敲除动物中缺乏这种蛋白质， 增加牙周骨流失的数量，加强了这种蛋白质调节 炎症所提出的应用将利用机械方法（过表达，沉默， 基因敲除动物、骨髓移植、蛋白质抑制）来研究IFI 16作为免疫调节剂的作用。 牙周宿主反应本项目将评估IFI 16作为牙周宿主反应的调节剂， 体外（SA 1）;我们建议探索a）IFI 16在体内阻碍炎症组织破坏和B）IFI 16在体内抑制炎症组织破坏。 利用目前可用的治疗剂（SA 2）;我们将确定IFI 16的主要细胞来源 负责炎症反应调节（SA 3）。虽然目前没有治疗方法 具体地靶向IFI 16，存在靶向AIM 2-炎性体产物的可用药物，例如 caspase-1抑制剂。这些实验的长期目标是更好地理解 牙周组织的破坏。Marchesan博士的研究将为 了解牙周组织破坏中的炎性小体调节，并允许开发一种 一个新的未来项目，探索炎性小体和潜在的治疗牙周炎的年底 这五年的融资期。