Center of Research Translation on the Osteoimmunology of Bone Infection

骨感染骨免疫学研究翻译中心

• 批准号: 10247748
• 负责人: Edward M. Schwarz
• 金额: $ 114万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247748
• 关键词: 3D Print; Address; Advisory Committees; Algorithms; Antibiotics; Antibodies; Award; Biocompatible Materials; Biological Assay; Biometry; Cessation of life; Clinical; Clinical Research; Communicable Diseases; Custom; Development; Diagnosis; Event; Evolution; Fostering; Genetic; Genus staphylococcus; Goals; Humoral Immunities; Image; Immune; Immune response; Immunity; Immunoassay; Immunology; Infection; Intervention; Joint Prosthesis; Knowledge; Life; Mediating; Molecular; Multiple Organ Failure; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Operative Surgical Procedures; Orthopedic Surgery; Orthopedics; Osteomyelitis; Pathogenesis; Pathology; Patient risk; Patients; Prevention; Primary Infection; Proteome; Replacement Arthroplasty; Research; Research Project Grants; Signal Pathway; Staphylococcus aureus; Staphylococcus aureus infection; Structure; Surgical Wound Infection; System; Tissue Engineering; Translating; Translational Research; base; bone; cell motility; cortical bone; drug discovery; improved; indexing; infection rate; innovation; joint infection; materials science; methicillin resistant Staphylococcus aureus; microbial; novel; novel diagnostics; osteoimmunology; programs; septic; trauma care

Abstract Prosthetic joint infection (PJI) is the bane of elective total joint replacement (TJR) surgery, of which the vast majority is caused by Staphylococcal species. Although the number of primary infections following TJR is low (1-5%), reinfection rates are very high (15-40%), which has led to the orthopaedic paradigm that S. aureus infection of bone is incurable. Additionally, PJI is known to be a non-random event that is largely determine by patient-specific factors, as infections are caused by only a few prevalent nosocomial strains (i.e. MRSA USA300), and implementation of the most rigorous surgical systems is incapable of reducing infection rates below 1%. Moreover, ~13% of patients infected with S. aureus become septic and die from multiorgan failure, while others recover with little intervention. To address these very significant issues, we propose the Center of Research Translation on the Osteoimmunology of Bone Infection (CoRTOBI), which is the evolution of two highly successful programs (AOTrauma Clinical Priority Program on Bone Infection (AO-CPP); and NIAMS P50 CORT AR54041 “Translating Molecular Signal Pathways to Orthopaedic Trauma Care”) that will be completed this year. To capitalize on the salient strengths of these programs, the CoRTOBI now proposes to advance and translate the major discoveries from the AO-CPP on S. aureus infection of bone and host immunity, using the proven administrative structure of the P50 CORT. These discoveries include: 1) S. aureus colonization of the osteocytic-canalicular network of live bone, 2) novel antibiotics that specifically target these mechanisms, which can be 3D-printed into custom spacers, 3) development of a custom multiplex Luminex assay to elucidate the immune proteome of S. aureus, and 4) identification of the anti-Isd vs. anti-Atl immune proteome ratio as a susceptible vs. protective index of host immunity against S. aureus. The proposed CoRTOBI will consist of an Administrative Core that will provide operational and fiscal management of the CoRTOBI, as well as a Clinical Research Sub-Core, a Biostatistics Sub-Core, an Enrichment Programs, and a Pilot and Feasibility Project Program. There are two Research Projects. Project 1 is focused on elucidating the mechanisms of S. aureus motility in bone and developing novel antibiotic impregnated 3D-printed spacers. Project 2 is focused on defining the susceptible vs. protective immune proteomes of Staphylococcus osteomyelitis and interventions for septic death. The Projects will be supported by an Osteoimmunology Research Core, which will provide state of the art imaging, biomaterial fabrication and immunoassay analyses. At the conclusion of this CoRTOBI we will have new knowledge on the microbial pathogenesis of bone infection and the host response. We will also develop novel diagnostics and interventions for patients with osteomyelitis.

抽象的 人工关节感染 (PJI) 是选择性全关节置换 (TJR) 手术的祸根 其中绝大多数是由葡萄球菌属引起的，尽管原发感染的数量较多。 随着 TJR 较低（1-5%），再感染率非常高（15-40%），这导致骨科 骨金黄色葡萄球菌感染是无法治愈的范例，此外，已知 PJI 是一种非随机的感染。 事件很大程度上取决于患者的具体因素，因为感染仅由少数几个因素引起 流行的医院菌株（即 MRSA USA300），并实施最严格的手术 此外，约 13% 的感染链球菌患者的感染率无法降低到 1% 以下。 金黄色葡萄球菌会出现败血症并死于多器官衰竭，而其他金黄色葡萄球菌则只需很少的干预即可康复。 为了解决这些非常重要的问题，我们建议建立研究翻译中心 骨感染骨免疫学 (CoRTOBI)，这是两种非常成功的方法的演变 计划（AOTrauma 骨感染临床优先计划 (AO-CPP)；和 NIAMS P50 CORT AR54041“将分子信号通路转化为骨科创伤护理”）即将完成 今年，为了充分利用这些计划的显着优势，CoRTOBI 现在建议： 推进并转化 AO-CPP 关于骨和宿主金黄色葡萄球菌感染的重大发现 免疫，使用 P50 CORT 的经过验证的管理结构这些发现包括：1）S. 金黄色葡萄球菌定植于活骨的骨细胞-小管网络，2) 新型抗生素 专门针对这些机制，可以将其 3D 打印到定制垫片中，3) 开发 用于阐明金黄色葡萄球菌免疫蛋白质组的定制多重 Luminex 测定，以及 4) 鉴定 抗 Isd 与抗 Atl 免疫蛋白质组比率作为宿主免疫的易感性与保护指数 拟议的 CoRTOBI 将包含一个管理核心，该核心将提供 CoRTOBI 的运营和财务管理，以及临床研究子核心、 生物统计学子核心、浓缩计划以及试点和可行性项目计划。 两个研究项目。项目 1 的重点是阐明金黄色葡萄球菌的运动机制。 项目 2 的重点是定义骨和新型抗生素浸渍 3D 打印垫片。 葡萄球菌骨髓炎的易感性与保护性免疫蛋白质组及干预措施 这些项目将得到骨免疫学研究核心的支持，该核心将 最后，提供最先进的成像、生物材料制造和免疫分析。 通过这个 CoRTOBI，我们将对骨感染的微生物发病机制和 我们还将为骨髓炎患者开发新的诊断和干预措施。