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.)
The proposed research aims to identify novel imaging measures of osteoarthritis using new technology, an ultra high field strength MRI scanner. The results will improve physicians' and scientists' understanding of how osteoarthritis develops and could suggest new ways to diagnose early osteoarthritis, as well as monitor and predict disease progression.
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