Development and MRI characterization of a goat model of human osteochondrosis

人类骨软骨病山羊模型的开发和 MRI 表征

• 批准号: 9270637
• 负责人: Ferenc Toth
• 金额: $ 13万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270637
• 关键词: Address; Adolescent; Affect; Albert Einstein Cancer Center; American; Animal Disease Models; Animal Model; Animals; Architecture; Area; Award; Biological Markers; Biomedical Research; Blood; Blood Vessels; Blood specimen; Cartilage; Cartilage Matrix; Chairperson; Characteristics; Childhood; Clinical; Collaborations; Collagen; Complex; Defect; Degenerative polyarthritis; Development; Diagnosis; Disease; Distal; Doctor of Philosophy; Early Diagnosis; Educational process of instructing; Ensure; Euthanasia; Evaluation; Extracellular Matrix; Failure; Family suidae; Femur; Future; Goat; Gold; Grant; Growth; Histologic; Histological Techniques; Histology; Human; Image; Imaging Techniques; Immobilization; Immunohistochemistry; Interdisciplinary Study; International; Interruption; Joints; Knowledge; Laboratories; Laboratory Research; Left; Lesion; Lesion by Stage; Life; MRI Scans; Magnetic Resonance; Magnetic Resonance Imaging; Medical; Medicine; Mentors; Methods; Minnesota; Modeling; Morphology; Motion; Musculoskeletal; Nature; Necrosis; Operative Surgical Procedures; Orthopedic Surgery procedures; Orthopedics; Osteochondritis Dissecans; Osteochondritis juvenilis; Osteochondrosis; Pathogenesis; Pathologist; Pathology; Population; Postdoctoral Fellow; Postoperative Period; Preparation; Principal Investigator; Process; Proteoglycan; Radiology Specialty; Research; Research Infrastructure; Research Personnel; Resources; Sampling; Secondary to; Signaling Molecule; Site; Staining method; Stains; Surgeon; Surgical Models; Synovial Fluid; Techniques; Testing; Tissues; Training; Training Programs; Treatment Protocols; Universities; Validation; Vascular Endothelial Growth Factors; Vascular blood supply; Veterinary Medicine; Work; biomarker evaluation; biomarker identification; bone; career; cartilaginous; college; comparative; computerized data processing; density; disease diagnosis; ex vivo imaging; experience; graduate student; healing; human disease; imaging modality; improved; in vivo imaging; individual patient; insight; instrumentation; long bone; magnetic field; member; mid-career faculty; multidisciplinary; novel; professor; prospective test; public health relevance; research facility; skills; subchondral bone; young adult

 DESCRIPTION (provided by applicant): This proposal describes a five year training program to prepare the applicant for a career as an independent researcher in comparative orthopaedics. The principal investigator holds a veterinary degree, and obtained his PhD in the field of comparative and experimental medicine. He has extensive surgical training, is a member of the American College of Veterinary Surgeons, and is currently employed as a postdoctoral fellow studying osteochondrosis (OC) using high field MRI techniques at the University of Minnesota. The proposed research aims to further our understanding of the pathogenesis, and enhance diagnosis and treatment of OC, a developmental orthopaedic disease that primarily affects young athletes. Osteochondrosis is characterized by the formation of loose, intra-articular (osteo)cartilaginous fragments, which, if left untreated, commonly result in osteoarthritis later i life. Dr. Cathy Carlson, a veterinary pathologist and internationally recognized expert on OC, will serve as the primary mentor of the candidate. Dr. Carlson is the director of an institutional training grant (T32OD010993, "Comparative Medicine and Pathology Training") and has trained numerous graduate students. Due to the multidisciplinary nature of the proposed studies, two additional co-mentors with various fields of expertise are included in the mentoring team: Dr. Michael Garwood, professor of radiology, Associate Director of the Center for Magnetic Resonance Research, which is a world renowned high field MRI research facility; and Dr. Denis Clohisy, professor and chairman, Department of Orthopedic Surgery. Dr. Troy Trumble, Associate Professor, Department of Veterinary Population Medicine will serve as a collaborator during the award period. This group of mentors and collaborator will ensure that the candidate will gain sufficient experience with: 1) the use of animal models of human disease; 2) histological techniques used to evaluate musculoskeletal tissues; 3) grantsmanship skills; 4) current and developing techniques in musculoskeletal MRI; 5) evaluation of biomarkers of orthopedic disease; and 6) advanced clinical and teaching techniques. Research will be focused on three aims: 1.) characterization of vascular architecture at predilection sites of OC 2.) development of a goat model of human OC 3.) validation of novel MRI techniques and identification of biomarkers capable of diagnosing osteochondrosis in the early, subclinical stage. To achieve the first aim, predilection sites and non-predilection sites of OC will be imaged using novel MRI sequences. To achieve our second aim, vascular supply to the epiphyseal cartilage of a well-defined area of the distal femur will be surgically interrupted in juvenile goas to create an area of cartilage necrosis (chondronecrosis), characteristic of subclinical osteochondrosis. Successful induction of this lesion will be evaluated by repeated imaging of the operated joint and by histological and immunohistochemical evaluation of joint samples obtained after euthanasia. During completion of the third aim, ability of novel MRI sequences to identify areas of the epiphyseal cartilage that have decreased vascular supply and areas of diminished proteoglycan and collagen content typical of early osteochondrosis lesions will be evaluated. Surgically induced lesions will be evaluated in goats and naturally occurring disease will be investigated in pigs. To validate MRI findings, samples will be processed for histology and serially sectioned in a plane matching that of the MRI scans. Sections (special stains and immunohistochemistry preparations) will be evaluated to identify changes in matrix composition consistent with osteochondrosis and to compare histological findings with (semi)quantitative MRI results. Synovial fluid and blood samples from goats with induced OC lesions will also be collected and evaluated to identify biomarkers of early OC lesions. The University of Minnesota is an ideal setting for the completion of the proposed research. The College of Veterinary Medicine provides the candidate access to state-of-the-art large and small animal surgical suites staffed with board certified surgeons, anesthesiologists and trained technical help. A 3T GE MRI scanner is also available on site for use. Dr. Carlson's laboratory is a well-developed resource for histological/morphological techniques, particularly in the area of bone and cartilage research. Close collaboration with the Center for Magnetic Resonance Research, an interdepartmental and interdisciplinary research laboratory, providing state-of-the-art instrumentation, expertise, and infrastructure enables the candidate to do basic and applied biomedical research using the unique capabilities provided by high field MRI. Finally, interaction with human orthopedic surgeons and researchers are enhanced by attendance at the Department of Orthopedic Surgery Grand Rounds held weekly.

 描述（由申请人提供）：该提案描述了一个为期五年的培训计划，旨在为申请人作为比较骨科独立研究员的职业做好准备。主要研究者拥有兽医学位，并获得比较和实验医学领域的博士学位。他接受过广泛的外科培训，是美国兽医学院的成员，目前在明尼苏达大学担任博士后研究员，使用高场 MRI 技术研究骨软骨病 (OC)。拟议的研究旨在进一步了解 OC 的发病机制，并加强对 OC 的诊断和治疗，OC 是一种主要影响年轻运动员的发育性骨科疾病。骨软骨病的特点是形成松散的关节内（骨）软骨碎片，如果不及时治疗，通常会在以后的生活中导致骨关节炎。兽医病理学家、国际公认的 OC 专家 Cathy Carlson 博士将 担任候选人的主要导师。卡尔森博士是机构培训补助金（T32OD010993，“比较医学和病理学培训”）的主任，并培养了众多研究生。由于拟议研究的多学科性质，指导团队中还包括两名具有不同专业领域的共同导师：Michael Garwood 博士，放射学教授，磁共振研究中心副主任，该中心是世界著名的高场 MRI 研究机构； Denis Clohisy 博士，骨科教授兼主任。兽医人口医学系副教授 Troy Trumble 博士将在颁奖期间担任合作者。这组导师和合作者将确保候选人在以下方面获得足够的经验：1）使用人类疾病的动物模型； 2）用于评估肌肉骨骼组织的组织学技术； 3）资助技巧； 4）当前和正在发展的肌肉骨骼MRI技术； 5）骨科疾病生物标志物评价； 6）先进的临床和教学技术。研究将集中于三个目标：1.) OC 好发部位血管结构的表征 2.) 开发人类 OC 的山羊模型 3.) 验证新型 MRI 技术并鉴定能够在早期、亚临床阶段诊断骨软骨病的生物标志物。为了实现第一个目标，将对 OC 的好发部位和非好发部位进行成像 使用新颖的 MRI 序列。为了实现我们的第二个目标，将通过手术中断青少年股骨远端明确区域的骨骺软骨的血管供应，以产生软骨坏死区域（软骨坏死），这是亚临床骨软骨病的特征。将通过对手术关节进行重复成像以及对安乐死后获得的关节样本进行组织学和免疫组织化学评估来评估这种病变的成功诱导。在完成第三个目标的过程中，将评估新型 MRI 序列识别血管供应减少的骨骺软骨区域以及早期骨软骨病病变典型的蛋白多糖和胶原含量减少区域的能力。将在山羊中评估手术引起的病变，并在猪中研究自然发生的疾病。为了验证 MRI 结果，将对样本进行组织学处理，并在与 MRI 扫描相匹配的平面上进行连续切片。将评估切片（特殊染色和免疫组织化学制剂），以确定与骨软骨病一致的基质成分变化，并将组织学结果与（半）定量 MRI 结果进行比较。还将收集并评估诱发 OC 损伤的山羊的滑液和血液样本，以确定早期 OC 损伤的生物标志物。明尼苏达大学是完成拟议研究的理想场所。兽医学院为候选人提供最先进的大型和小型动物手术室，配备了经过委员会认证的外科医生、麻醉师和训练有素的技术帮助人员。现场还提供 3T GE MRI 扫描仪供使用。卡尔森博士的实验室拥有完善的组织学/形态学技术资源，特别是在骨和软骨研究领域。与磁共振研究中心（一个跨部门和跨学科的研究实验室）密切合作，提供最先进的仪器、专业知识和基础设施，使候选人能够利用高场 MRI 提供的独特功能进行基础和应用生物医学研究。最后，参加每周举行的骨科外科大查房活动可以增强与人类骨科医生和研究人员的互动。