Host-pathogen interactions during osteomyelitis

骨髓炎期间宿主与病原体的相互作用

• 批准号: 9273893
• 负责人: JAMES E CASSAT
• 金额: $ 18.45万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273893
• 关键词: Academic Medical Centers; Acinetobacter baumannii; Address; Adult; Affect; Animal Model; Antibiotic Resistance; Antibiotics; Arkansas; Award; Bacillus anthracis; Bacteria; Bacterial Infections; Bacterial Proteins; Biological Models; Biology; Blood Vessels; Bone remodeling; Cell Death; Cells; Child; Childhood; Chronic; Clinical; Communicable Diseases; Comorbidity; Data; Debridement; Deep Vein Thrombosis; Development; Diabetes Mellitus; Doctor of Medicine; Doctor of Philosophy; Environment; Experimental Models; Fellowship; Flow Cytometry; Fostering; Fracture; Funding; Generations; Genes; Goals; High-Throughput Nucleotide Sequencing; Homeostasis; Human; Image; Immune; Immune response; Immune system; Immunology; In Vitro; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Institutes; Integration Host Factors; International; Intervention; Knowledge; Libraries; Mediating; Medical; Mentors; Microbe; Modeling; Molecular; Morbidity - disease rate; Multi-Drug Resistance; Mus; Musculoskeletal; Mutation; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Osteomyelitis; Pathogenesis; Pathologic; Pathway interactions; Patients; Penetration; Physicians; Physiology; Play; Population; Prevalence; Proteome; Publishing; Recruitment Activity; Refractory; Research; Resolution; Resources; Role; Scholarship; Science; Scientist; Septicemia; Signal Transduction; Site; Staphylococcus aureus; Stem cells; Techniques; Testing; Therapeutic; Training; Translational Research; Trauma; Universities; Virulence Factors; adaptive immune response; antimicrobial; bacterial resistance; bone; bone turnover; career; compliance behavior; cytotoxic; experience; experimental study; fitness; imaging modality; in vivo; in vivo Model; innovation; interdisciplinary approach; member; mouse model; mutant; novel therapeutics; osteoblast differentiation; pathogen; public health relevance; response; skills; tool; vaccine development

DESCRIPTION (provided by applicant): Osteomyelitis is a common and debilitating infection of bone that affects healthy children and adults, as well as those with comorbidities such as diabetes and musculoskeletal trauma. Bacterial pathogens, notably Staphylococcus aureus, are the most common causes of osteomyelitis. Treatment options for bone infections are limited by both the increasing prevalence of multi-drug resistant bacterial pathogens, as well as pathogen- induced changes in bone remodeling that limit antibiotic penetration into the infection site. Even with prolonged administration of appropriate antimicrobial therapy, patients suffering from osteomyelitis often experience significant morbidity, including bone fractures, deep venous thrombosis, and septicemia. Osteomyelitis therefore necessitates aggressive interventions such as surgical debridement, after which some patients still progress to chronic infection. The mechanisms by which bacterial pathogens induce and sustain osteomyelitis, trigger detrimental changes in bone remodeling, and evade host immune responses in the bone are poorly understood. Likewise, the host immune responses that protect bone from osteomyelitis, or that contribute to pathogen-induced changes in bone remodeling have not been fully delineated. Finally, how bone homeostasis is modulated by infectious and inflammatory signals is not well defined. The goals of this proposal are to understand how bacterial virulence factors perturb bone homeostasis (Aim 1), to delineate host immune responses that either promote clearance of bacterial pathogens from bone, or contribute to pathogen-induced changes in bone remodeling (Aim 2), and to define bacterial factors that are critical for survival within the bone (Aim 3). Successful completion of the proposed Aims will significantly enhance an understanding of the pathogenesis of osteomyelitis, define mechanisms governing bone homeostasis during infection and inflammation, and meet the need for new therapies that treat osteomyelitis and counteract pathogen-induced changes in bone remodeling. Dr. James Cassat is currently a Clinical Fellow in Pediatric Infectious Diseases at Vanderbilt University Medical Center. He completed the M.D. and Ph.D. degrees at the University of Arkansas for Medical Sciences prior to his clinical training at Vanderbilt. During clinical fellowship, Dr. Cassat has focused his research efforts on understanding the pathogenesis of osteomyelitis, one of the most common invasive bacterial infections in children. Dr. Cassat has created innovative tools to model the host-pathogen interface during osteomyelitis, including a new animal model that utilizes high resolution tomographic imaging to quantify changes in bone remodeling during osteomyelitis. These tools, recently published in Cell Host and Microbe, enabled generation of substantial preliminary data for the studies outlined in this application. In completion of the proposed Aims, Dr. Cassat will draw upon greater than 10 years of experience studying the molecular pathogenesis of S. aureus, but will also gain new proficiencies in translational imaging modalities, immunology, advanced flow cytometry, and bone biology. The compilation of these skills will facilitate Dr. Cassat's development into an independently-funded pediatric physician-scientist, and will ultimately enable a translational research career that addresses an important clinical problem while seeking to define the pathways that govern musculoskeletal homeostasis in the setting of infection and inflammation. His professional development will be guided by an inter-disciplinary scholarship oversight committee, chaired by his mentor Dr. Eric Skaar. Dr. Skaar is an internationally recognized expert in host-pathogen interactions, with a specific focus on the important human pathogens S. aureus, Acinetobacter baumannii, and Bacillus anthracis. Additional members of Dr. Cassat's scholarship oversight committee will facilitate the acquisition of new techniques and knowledge throughout the award period, while fostering important collaborative efforts. These members include experts in the innate and adaptive immune responses to human pathogens (Dr. John Williams and Dr. Buddy Creech), translational imaging modalities (Dr. Charles Manning), and fundamental bone biology (Dr. Florent Elefteriou). Completion of the proposed studies will require a multi-disciplinary approach that capitalizes on Vanderbilt's strengths in the study of host-pathogen interactions, translational imaging sciences, immunology, and bone biology. The outstanding resources of the Division of Pediatric Infectious Diseases, The Vanderbilt Center for Bone Biology, and the Vanderbilt University Institute of Imaging Sciences will provide Dr. Cassat a unique and stimulating environment for professional development. In total, Vanderbilt is the ideal environment for completion of the proposed studies.

描述（由申请人提供）：骨髓炎是影响健康儿童和成人的常见且使人衰弱的感染，以及患有糖尿病和肌肉骨骼创伤等合并症的骨骼感染。细菌病原体，尤其是金黄色葡萄球菌，是骨髓炎的最常见原因。骨骼感染的治疗选择受到多药耐药细菌病原体的患病率的增加，以及病原体诱导的骨骼重塑的变化，从而将抗生素渗透到感染部位。即使长期服用适当的抗菌治疗，患有骨髓炎的患者也经常出现明显的发病率，包括骨折，深静脉血栓形成和败血病。因此，骨髓炎需要进行积极的干预措施，例如手术清创术，此后一些患者仍会发展为慢性感染。细菌病原体诱导和维持骨髓炎的机制，引发骨骼重塑的有害变化以及逃避骨骼中的宿主免疫反应的变化知之甚少。同样，宿主免疫反应可保护骨骼免受骨髓炎的影响，或者尚未完全描绘出病原体诱导的骨骼重塑变化的宿主免疫反应。最后，骨体内平衡如何受到传染和炎症信号的调节。该提案的目标是了解细菌毒力因素如何扰动骨稳态（AIM 1），以描绘宿主免疫反应，以促进从骨骼中清除细菌病原体的清除，或者导致病原体诱导的骨骼重塑的变化（AIM 2）（AIM 2），并定义对骨骼内生存至关重要的细菌因子（AIM 3）。成功完成所提出的目标将显着增强对骨髓炎的发病机理的理解，定义控制骨骼稳态和炎症期间骨骼稳态的机制，并满足治疗骨髓炎的新疗法以及对抗骨髓炎的新疗法的需求。 詹姆斯·卡萨特（James Cassat）博士目前是范德比尔特大学医学中心的小儿传染病临床研究员。他完成了医学博士学位和博士学位阿肯色大学在范德比尔特（Vanderbilt）接受临床培训之前的医学科学学位。在临床研究金期间，卡萨特博士将研究工作集中在理解骨髓炎的发病机理上，骨髓炎是儿童最常见的侵入性细菌感染之一。卡萨特博士创建了创新的工具来对骨髓炎期间的宿主 - 病原体界面进行建模，其中包括一种新的动物模型，该模型利用高分辨率层析成像来量化骨髓炎期间骨骼重塑的变化。这些工具最近发表在细胞宿主和微生物中，可以生成本应用程序中概述的研究的实质性初步数据。在完成拟议的目标时，卡萨特博士将借鉴研究金黄色葡萄球菌分子发病机理的10年以上的经验，但也将获得转化成像方式，免疫学，晚期流式细胞仪和骨生物学方面的新能力。这些技能的汇编将促进卡萨特博士的发展成独立资助的儿科医生 - 科学家，并最终将使转化研究职业能够解决一个重要的临床问题，同时试图定义在感染和炎症的环境中控制肌肉骨骼稳态的途径。他的职业发展将由他的导师埃里克·斯卡尔（Eric Skaar）博士主持的跨学科奖学金监督委员会指导。 Skaar博士是国际公认的宿主 - 病原体相互作用的专家，特别关注了重要的人类病原体S.金黄色葡萄球菌，鲍曼尼杆菌和炭疽芽孢杆菌。卡萨特博士奖学金监督委员会的其他成员将在整个奖励期间促进新技术和知识的获取，同时促进重要的合作努力。这些成员包括对人类病原体（John Williams博士和Buddy Creech博士），翻译成像方式（Charles Manning博士）和基本骨生物学（Florent Elefteriou博士）的先天和适应性免疫反应的专家。 拟议研究的完成将需要一种多学科的方法，该方法在研究宿主 - 病原体相互作用，翻译成像科学，免疫学和骨骼生物学的研究中利用了范德比尔特的优势。小儿传染病，范德比尔特骨骼生物学中心和范德比尔特大学成像科学研究所的杰出资源将为卡萨特博士提供一个独特而刺激的专业发展环境。总的来说，范德比尔特是完成拟议研究的理想环境。