Osteoarthritis: Identification of Novel Imaging Biomarkers via 23Na/1H MRI at 7 T

描述(申请人提供)：这项K23指导型以患者为导向的研究职业发展奖提案的目标是为医学博士Gregory Chang提供一段有重点的培训期，在此期间他将获得技能，过渡到转化性生物医学成像研究的独立研究员，专注于肌肉骨骼疾病。该职业发展计划旨在加强张博士在三个方面的技能和知识，以便他可以帮助弥合尖端成像研究和日常临床实践之间的差距。这些领域包括：1)骨关节炎的生物学和临床意义(发病机制、生物力学考虑、风湿学和骨科诊断和治疗中的问题)；2)先进的磁共振成像(MRI)技术(磁共振物理学、脉冲序列设计、图像处理)，以及3)设计以患者为导向的临床放射学研究(生物统计学、流行病学、临床研究设计、科学完整性培训和负责任的研究进行)。这将通过世界级教师的密切指导以及多学科课程和研讨会来实现，这些课程和研讨会将在纽约大学(NYU)的各种机构举行。导师将由Steve Abramson，M.D.，Peter Walker，Ph.D.，Ravinder Regatte，Ph.D.和Michael Recht，M.D.提供，他们在骨关节炎生物学、生物力学、生物标记物和成像研究方面的贡献世界闻名。其他关键顾问詹姆斯·巴布博士、克里斯蒂安·格拉泽医学博士和普纳姆·萨哈博士将分别带来生物统计学、临床研究设计、骨关节炎成像和图像处理方面的专业知识。多学科课程和研讨会将在以下地点举行：1)纽约大学医学院生物统计学、放射学、风湿病和整形外科系，2)纽约大学肌肉骨骼疾病英才中心，3)纽约大学NIH资助的临床和翻译科学研究所(CTSI)和纽约市卫生与医院公司(HHC)。最后，咨询委员会将向张博士提供季度反馈，并评估他的进展情况，以便他在职业发展奖励期结束前获得成功申请RO1资金所需的记录和初步数据。该研究计划的目标是通过超高场(UHF)7特斯拉(T)钠和质子核磁共振技术识别骨关节炎(OA)的新的微结构和生化成像生物标记物。如果成功，预期的结果将加强医生和科学家对OA发病机制的了解，并为早期诊断和更准确地监测/预测疾病进展提供一种潜在的非侵入性手段。骨性关节炎表现为关节软骨的退变(最初蛋白多糖含量降低，随后厚度减小)和软骨下骨的损伤(微骨折、骨赘)。然而，目前用于诊断骨关节炎的成像技术(X光片，1.5-3T的常规MRI)是有限的，因为它们只能在很大程度上不可逆转的情况下检测到宏观的结构关节损伤。这项建议的总体假设是，高分辨率的7T钠和质子MRI将能够检测和量化不同阶段的OA受试者软骨厚度、体积和蛋白多糖含量的轻微减少以及软骨下松质骨微结构的轻微变化(骨小梁厚度、数量、分离、板棒比和连通性)。超高频磁共振扫描仪的主要优势是可获得更高的内部信号，这使得可以通过钠核磁共振测量软骨蛋白多糖含量，以及通过质子核磁共振对软骨和骨骼微结构进行高分辨率成像。使用这种独特的解剖和生理成像相结合的方法，我们将招募健康的早期骨关节炎(凯尔格伦-劳伦斯放射学1-2级)和高级骨关节炎(凯尔格伦-劳伦斯3-4级)受试者，并执行以下具体目标。在具体目标1中，我们将确定软骨和骨骼的7T磁共振测量是否可以检测疾病的存在和疾病的严重程度(区分健康的和早期的骨性关节炎患者，以及早期的骨性关节炎患者和晚期的骨性关节炎患者)。在具体目标2中，我们将确定软骨和骨骼的7个T磁共振测量的纵向变化是否指示了参照标准(X线片、常规MRI和临床问卷)评估的疾病进展。最后，在特定的目标3中，我们将确定软骨和骨骼的7T磁共振测量的基线值是否如参考标准(X线片、常规MRI和临床问卷)评估的那样预测疾病的进展。总而言之，通过多学科课程、世界级教师的密切指导以及在丰富的学术环境中参与精心设计的研究项目，Chang博士将提高他利用新的MRI技术进行面向患者的临床研究的能力，促进他转变为转译肌肉骨骼成像研究的独立研究员。)

DESCRIPTION (provided by applicant): The goal of this K23 Mentored Patient-Oriented Research Career Development Award proposal is to provide Gregory Chang, M.D., with a focused training period during which he will gain the skills to transition into an independent investigator in translational biomedical imaging research with a focus on musculoskeletal disease. The career development plan aims to strengthen Dr. Chang's skills and knowledge in three areas so that he may help bridge the gap between cutting edge imaging research and daily clinical practice. These areas include: 1) biology and clinical implications of osteoarthritis (pathogenesis, biomechanical considerations, rheumatologic and orthopedic issues in diagnosis and treatment); 2) advanced magnetic resonance imaging (MRI) techniques (MR physics, pulse sequence design, image processing), and 3) design of patient-oriented, clinical radiology studies (biostatistics, epidemiology, clinical study design, training in scientific integrity and the responsible conduct of research). This will be achieved via close mentoring by world-class faculty and via multidisciplinary coursework and seminars, which will take place across a diversity of institutions at New York University (NYU). Mentorship will be provided by Steve Abramson, M.D., Peter Walker, Ph.D., Ravinder Regatte, Ph.D., and Michael Recht, M.D., who are world- renowned for their contributions to osteoarthritis biology, biomechanics, biomarker, and imaging research. Additional key consultants James Babb, Ph.D., Christian Glaser, M.D., and Punam Saha, Ph.D., will bring expertise in biostatistics, clinical study design, osteoarthritis imaging, and image processing, respectively. Multidisciplinary coursework and seminars will take place at: 1) the NYU School of Medicine within the Departments of Biostatistics, Radiology, Rheumatology, and Orthopedic Surgery, 2) the NYU Center of Excellence on Musculoskeletal Disease, and 3) the NIH-funded Clinical and Translational Science Institute (CTSI) of NYU and the New York City Health and Hospitals Corporation (HHC). Finally, an advisory committee will provide quarterly feedback to Dr. Chang and assess his progress so that he will have the track record and preliminary data required to successfully apply for RO1 funding by the end of the career development award period. The goal of the research plan is to identify novel microstructural and biochemical imaging biomarkers of osteoarthritis (OA) via ultra high field (UHF) 7 Tesla (T) sodium and proton MRI techniques. If successful, the expected results will enhance physicians' and scientists' understanding of OA pathogenesis, and suggest a potential noninvasive means for early diagnosis and more accurate monitoring/prediction of disease progression. OA is manifested by degeneration in articular cartilage (initially decreased proteoglycan content, followed by reduced thickness) and damage to subchondral bone (microfractures, osteophytosis). However, current imaging techniques utilized to diagnose osteoarthritis (radiographs, conventional MRI at 1.5-3T) are limited in that they can only detect macroscopic structural joint damage when it is largely irreversible. The overall hypothesis of this proposal is that high resolution, 7T sodium and proton MRI will be able to detect and quantify subtle decreases in cartilage thickness, volume, and proteoglycan content and subtle alterations in subchondral trabecular bone micro-architecture (trabecular thickness, number, separation, plate-to-rod ratio, and connectivity) in subjects with varying stages of OA. The main advantage of the UHF MR scanner is the increased intrinsic signal available, which allows measurement of cartilage proteoglycan content via sodium MRI as well as high resolution imaging of cartilage and bone microstructure via proton MRI. Using this unique combined anatomic and physiologic imaging approach, we will recruit healthy, early OA (Kellgren Lawrence radiographic grade 1-2), and advanced OA (Kellgren- Lawrence grade 3-4) subjects and perform the following specific aims. In specific aim 1, we will determine whether 7T MR measures of cartilage and bone can detect disease presence and disease severity (distinguish healthy from early OA subjects, and early OA from advanced OA subjects). In specific aim 2, we will determine whether longitudinal changes in 7 T MR Measures of cartilage and bone are indicative of disease progression as assessed by reference standards (radiographs, conventional MRI, and clinical questionnaires). Finally, in specific aim 3, we will determine whether baseline values of 7T MR measures of cartilage and bone predict disease progression as assessed by reference standards (radiographs, conventional MRI, and clinical questionnaires). In summary, via multidisciplinary coursework, close mentoring by world-class faculty, and participation in a carefully-designed research project in a rich academic environment, Dr. Chang will improve upon his ability to conduct patient-oriented, clinical studies utilizing novel MRI techniques, facilitating his transition into an independent investigator in translational musculoskeletal imaging research.)