This is an application for a K23 Career Development Award (CDA) for Dr. AnneMarie Brescia, a pediatric rheumatologist at the Nemours/ AI duPont Hospital for Children (Nemours). Although she has had training in molecular biology techniques during her 2 years as a post-doctoral fellow at NIAMS/NIH, she needs specific training in statistical methods, bioinformatics and the process of biomarker development, in addition to guidance on grantsmanship and scientific writing. Her short-term career goals are to focus on training in translational research and acquire the tools needed to achieve her long-term career goals of being an independent clinical translational researcher able to help shape future treatment for children with arthritis. This CDA will allow her to evolve from primarily a clinician conducting some research into a clinician scientist, poised to answer essential questions which will translate into better, more personal, care for patients. She has laid out a plan to allow her o acquire these skill sets through (1) formal didactic instruction;(2) research preceptorships;(3) educational activities at The University of Pennsylvania (Penn) and Nemours;and (4) collaboration with experts in the field. Her mentors will be Dr. Kathleen Sullivan (primary mentor), a pediatric rheumatologist who is Chief of Allergy and Immunology at The Children's Hospital of Philadelphia (CHOP) and Dr. Carlos Rose (co-mentor), a pediatric rheumatologist who is Chief of Rheumatology at Nemours and chairman of the Nemours IRB. She has assembled an advisory committee that also includes Dr. Edward Behrens, a currently R01 funded researcher who brings content expertise in pediatric rheumatology, and Dr. Birgit Kovacs, an adult rheumatologist who brings extensive knowledge of translational research and biomarker development. Dr. Brescia's project focuses on causes of disability in Oligoarticular Juvenile Idiopathic Arthritis (JIA), the most common subtype of the most common rheumatic disease of childhood. Disability results from two sources, namely extension to a polyarticular course, termed extended oligoarticular disease, and local deformities associated with altered growth. Persistent oligoarthritis affects up to 4 joints throughout the disease course while extended oligoarthritis affects a cumulative total of 5 joints or more after the first 6 months of disease. Since disease progression increases the risk for disability, early prediction of this course is essential;unfortunately, no reliable clinical or laboratory predictors have been established. Within this proposal, Dr. Brescia will develop synovial biomarker panels that predict disease progression from persistent to extended oligoarticular JIA (Aim 1). The project will also focus on the role of the JIA fibroblast-like synoviocytes in the localized altered growth seen in oligoarticular JIA (Aim 2). Synovial biomarkers will lead to better risk stratification and more effective targeting of therapeutics. Completion of these aims will lead to a larger, prospective study in which the rapid assessment of synovial fluid samples early in the course of disease will be used to predict disease course and patients will be followed over time to validate the positive and negative predictive values of the panel. In addition, the insight gained into the role of the dysregulated TGF?/BMP4 signaling in the localized altered growth will allow Dr. Brescia to study interventions that address this phenotype, either enhancing it if it is reparative or blockin it if it is detrimental. There is a rich academic environment available for Dr. Brescia to achieve her goals. From the inception of this project, she has worked closely with Dr. Suzanne McCahan, a biostatistician within Nemours Bioinformatics Core, and will continue to do so. She has access to tremendous resources at Nemours including translational science seminars, journal clubs, and division of rheumatology clinical meetings, in addition to research and education courses. The mentorship at CHOP opens up avenues for collaborations and experts in translational research. Dr. Brescia will complete the Clinical Research Certificate Program offered by Penn, which includes courses in Biostatistics, Proposal Development, Scientific and Ethical Conduct, and Intro to Bioinformatics, in addition to three web-based courses: Bioethics Training Program, Patient-Oriented Research Certification Program and HIPAA Privacy Education Program, in addition to Collaborative Institutional Training Initiative (CITI) programs: 1) Responsible Conduct of Research and 2) Protection of Human Subjects. She will benefit from Nemours participation in several large research partnerships, Delaware Health Sciences Alliance (DHSA), Delaware Clinical and Translational Research Program (DE-CTR), and Delaware IDeA Network of Biomedical Research Excellence (DE-INBRE) that significantly broaden the available intellectual resources available to her. Finally, this proposed project is superbly suited to serve as a training vehicle for Dr. Brescia's maturation as a translational researcher in the field of pediatric rheumatology. This training will allow Dr. Brescia to successfully compete for R01 funding for a prospective trial of using synovial fluid biomarkers to predict course in new onset juvenile idiopathic arthritis.

Public Health Relevance

Development of synovial biomarker panels allows us to provide families and patients with more complete information regarding prognosis and to make more informed decisions regarding treatment strategies. Addressing JIA as early as possible to prevent joint damage will in turn significantly improve the long-term functional outcome and life enjoyment of children with arthritis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Mao, Su-Yau
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Alfred I. Du Pont Hosp for Children
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Brescia, AnneMarie C; Simonds, Megan M; McCahan, Suzanne M et al. (2018) Prior to extension, Transcriptomes of fibroblast-like Synoviocytes from extended and Polyarticular juvenile idiopathic arthritis are indistinguishable. Pediatr Rheumatol Online J 16:3
Brescia, AnneMarie C; Simonds, Megan M; Sullivan, Kathleen E et al. (2017) Secretion of pro-inflammatory cytokines and chemokines and loss of regulatory signals by fibroblast-like synoviocytes in juvenile idiopathic arthritis. Proteomics Clin Appl 11: