Center of Research Translation on the Osteoimmunology of Bone Infection (CoRTOBI)

骨感染骨免疫学研究翻译中心 (CoRTOBI)

• 批准号: 10402963
• 负责人: Edward M. Schwarz
• 金额: $ 140.27万
• 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 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402963
• 关键词: 3-Dimensional; 3D Print; Address; Adjuvant; Advisory Committees; Algorithms; Antibiotic Therapy; Antibiotics; Antigens; Award; Bioinformatics; Biological Assay; Biometry; COVID-19 pandemic; Chemicals; Clinic; Clinical; Community Outreach; Consensus; Custom; Development; Diagnosis; Diagnostic; Educational workshop; Event; Fostering; Funding; Gene Expression Regulation; Genomics; Goals; Health Care Costs; Human Genetics; Image; Immune; Immune Evasion; Immune response; Immunity; Immunoassay; Immunodiagnostics; Implant; Incidence; Infection; Intellectual Property; Interest Group; International; Intervention; Joint Prosthesis; Knowledge; Legal patent; Microfabrication; Molecular; Mus; Musculoskeletal; ORALIT; Operative Surgical Procedures; Orthopedic Surgery; Orthopedics; Osteocytes; Osteomyelitis; Outcome; Outcome Measure; Pathogenesis; Pathogenicity; Patient risk; Patient-Focused Outcomes; Patients; Persons; Prophylactic treatment; Proteome; Publications; RNA vaccine; Race; Replacement Arthroplasty; Research; Research Personnel; Research Project Grants; Seminal; Staphylococcus aureus; Staphylococcus aureus infection; Surface; Technology; Testing; Therapeutic; Time; Translating; Translational Research; Translations; Vaccines; Virulent; Work; adverse outcome; antibiotic tolerance; antimicrobial; base; bone; clinical candidate; clinical translation; demographics; genetic strain; imprint; in vivo imaging; industry partner; ineffective therapies; innovation; innovative technologies; intravital microscopy; joint infection; meetings; microbial; mouse model; novel; novel diagnostics; osteoimmunology; outreach program; prevent; programs; response; small molecule inhibitor; standard of care; success

Abstract Bone infection caused by Staphylococcus aureus remains the bane of orthopaedic surgery, as diagnostics, prophylactics and treatments have significant shortcomings that result in catastrophic outcomes for patients, and crippling healthcare costs. Although the incidence of infection following primary total joint replacement (TJR) is low (~1%), reinfection rates are very high (15-40%), which has led to the orthopaedic paradigm that S. aureus infection of bone is incurable. Additionally, prosthetic joint infection (PJI) is known to be a non-random event that is largely determined by patient-specific factors. To address this, we proposed the original Center of Research Translation on the Osteoimmunology of Bone Infection (CoRTOBI) to test the hypotheses that: 1) there must be a reservoir of S. aureus that is not affected by standard of care treatments, and 2) the patient’s immune proteome against S. aureus antigens impacts the incidence and outcome of bone infection. Our work on this has resulted in innovative technologies that are being translated to the clinic by industry partners, and several seminal discoveries that we will continue to work on in this renewal, including: 1) S. aureus colonization of the osteocyte lacuno-canalicular network (OLCN) of live bone, 2) novel small molecule inhibitors that specifically target these mechanisms that can be 3D-printed into custom spacers as adjuvants to antibiotics, 3) development of a custom multiplex immunoassays to elucidate the immune proteome of S. aureus, 4) development of in vivo imaging to quantify “the race for the surface” of implants in real time, and 5) identification of anti-IsdB responses as susceptible immunity vs. anti-Gmd responses as protective immunity in mice and patients with culture confirmed S. aureus bone infection. Based on this success, we propose continuation of CoRTOBI with its Administrative Core that provides operational and fiscal management of the CoRTOBI, as well as a Biostatistics Sub-Core, an Enrichment Program, and a Pilot and Feasibility Project Program. We will also continue the Research Projects. Project 1 is focused on elucidating the mechanisms of S. aureus invasion of the OLCN, and developing novel antibiotic and adjuvant impregnated 3D-printed spacers. Project 2 is focused on elucidating the mechanism responsible for the susceptible immune proteome in patients, translating our discovery of five protective antigens with a novel multivalent mRNA vaccine, and bioinformatic assessment of patient-specific factors with the strain of S. aureus with which they are infected. The Projects will be supported by an Osteoimmunology Research Core, which will provide state of the art imaging, microfabrication and immunoassay analyses. The Core will also further innovate these technologies into novel outcome measures and enhance their clinical utility towards commercial products. At the conclusion of this CoRTOBI we will have in-depth knowledge of S. aureus OLCN invasion and immune evasion, as well as novel candidate clinical assays, antimicrobials and vaccines, to diagnose, prevent and treat the most serious bone infections, whose outcomes have not improved over the last half century.

抽象的 金黄色葡萄球菌引起的骨骼感染仍然是骨科手术的祸根，作为诊断，作为诊断， 预防药物和治疗具有重大缺点，导致患者的灾难性结果， 并削减医疗保健费用。虽然主要关节置换后感染事件 （TJR）较低（〜1％），再感染率很高（15-40％），这导致了S.的骨科范式。 骨骼的金黄色葡萄球菌感染是无法治愈的。此外，已知假体关节感染（PJI）是非随机 事件主要由患者特异性因素决定。为了解决这个问题，我们提出了原始中心 研究骨感染骨气免疫学（Cortobi）的研究翻译以检验假设 那就是：1）必须有一个不受护理标准治疗标准的金黄色葡萄球菌的水库，2） 患者针对金黄色葡萄球菌抗原的免疫蛋白酶会影响骨骼感染的事件和结果。 我们在这方面的工作导致了创新技术，这些技术被行业转化为诊所 合作伙伴，以及我们将继续在此续签中继续进行的几个发现，包括：1）S。 活骨的骨细胞lacuno-cancancarnicular网络（OLCN）的金黄色葡萄球菌定殖，2）新型小分子 专门针对这些机制的抑制剂，可以将3D打印到自定义垫片中作为调节器 抗生素，3）开发自定义多重免疫测定法，以阐明S.的免疫蛋白质组。 金黄色，4）体内成像的开发，以实时量化侵权的“表面竞赛”，5） 将抗ISDB反应鉴定为敏感的免疫（vs.抗GMD反应）作为保护性免疫（在 小鼠和培养患者证实了金黄色葡萄球菌的骨骼感染。基于这一成功，我们建议 Cortobi及其行政核心的延续，提供运营和财政管理 Cortobi，以及生物统计学子核，富集计划以及飞行员和可行性项目 程序。我们还将继续研究项目。项目1的重点是阐明 S.金黄色葡萄球菌入侵OLCN，并开发新型抗生素并调整浸渍的3D打印 垫片。项目2的重点是阐明负责易感免疫蛋白质组的机制 在患者中，用一种新型的多价mRNA疫苗转化了我们发现五种受保护的抗原，并 用感染的金黄色葡萄球菌的菌株对患者特异性因素的生物信息学评估。 这些项目将得到骨气免疫研究核心的支持，该研究核心将提供最先进的状态 成像，微作业和免疫测定分析。核心还将进一步创新这些技术 进入新的结果措施并增强其对商业产品的临床实用性。结论 在这种Cortobi中，我们将对金黄色葡萄球菌Olcn入侵和免疫进化有深入的了解以及 新颖的候选临床评估，抗菌和疫苗，以诊断，预防和治疗最严重的 骨骼感染，其结果在过去半个世纪没有改善。