Host-pathogen interactions during osteomyelitis

骨髓炎期间宿主与病原体的相互作用

基本信息

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
项目类别：
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

项目摘要

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）：骨髓炎是一种常见的、使人衰弱的骨骼感染，影响健康的儿童和成人，以及患有糖尿病和肌肉骨骼创伤等合并症的人。细菌病原体，特别是金黄色葡萄球菌，是骨髓炎的最常见原因。骨感染的治疗选择受到多重耐药细菌病原体日益流行以及病原体诱导的骨重塑变化的限制，这些变化限制了抗生素渗透到感染部位。即使长期给予适当的抗菌治疗，患有骨髓炎的患者也常常会出现严重的并发症，包括骨折、深静脉血栓形成和败血症。因此，骨髓炎需要积极的干预措施，例如手术清创，之后一些患者仍然进展为慢性感染。细菌病原体诱发和维持骨髓炎、引发骨重塑的有害变化以及逃避骨骼中宿主免疫反应的机制尚不清楚。同样，保护骨骼免受骨髓炎或导致病原体诱导的骨重塑变化的宿主免疫反应尚未完全阐明。最后，感染和炎症信号如何调节骨稳态尚不清楚。该提案的目标是了解细菌毒力因素如何扰乱骨稳态（目标 1），描绘宿主免疫反应，促进细菌病原体从骨中清除，或促进病原体诱导的骨重塑变化（目标 2），并确定对骨内生存至关重要的细菌因素（目标 3）。成功完成拟议目标将显着增强对骨髓炎发病机制的理解，定义感染和炎症期间控制骨稳态的机制，并满足治疗骨髓炎和抵消病原体诱导的骨重塑变化的新疗法的需求。詹姆斯·卡萨特博士目前是范德比尔特大学医学中心儿科传染病的临床研究员。他完成了医学博士和博士学位。在范德比尔特接受临床培训之前，他在阿肯色大学获得医学科学学位。在临床研究期间，卡萨特博士的研究重点是了解骨髓炎的发病机制，骨髓炎是儿童最常见的侵袭性细菌感染之一。卡萨特博士创建了创新工具来模拟骨髓炎期间的宿主-病原体界面，包括一种新的动物模型，该模型利用高分辨率断层扫描成像来量化骨髓炎期间骨重塑的变化。这些工具最近发表在《细胞宿主》和《微生物》杂志上，能够为本申请中概述的研究生成大量初步数据。在完成拟议的目标时，Cassat 博士将利用 10 多年研究金黄色葡萄球菌分子发病机制的经验，同时还将在转化成像模式、免疫学、先进流式细胞术和骨生物学方面获得新的熟练程度。这些技能的汇集将有助于卡萨特博士发展成为一名独立资助的儿科医师科学家，并最终实现转化研究生涯，解决重要的临床问题，同时寻求定义感染环境中控制肌肉骨骼稳态的途径和炎症。他的专业发展将受到跨学科奖学金监督委员会的指导，该委员会由他的导师埃里克·斯卡尔博士担任主席。 Skaar 博士是国际公认的宿主与病原体相互作用方面的专家，特别关注重要的人类病原体金黄色葡萄球菌、鲍曼不动杆菌和炭疽杆菌。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的先天性和适应性免疫反应（John Williams 博士和 Buddy Creech 博士）、转化成像模式（Charles Manning 博士）和基础骨生物学（Florent Elefteriou 博士）方面的专家。完成拟议的研究需要采用多学科方法，充分利用范德堡大学在宿主-病原体相互作用、转化成像科学、免疫学和骨生物学研究方面的优势。儿科传染病科、范德比尔特骨生物学中心和范德比尔特大学影像科学研究所的优秀资源将为卡萨特博士提供独特且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。