The major goal of this proposal is to attain clinical and translational research skills to become an excellent, independent investigator in rheumatology, with a focus in scleroderma. Systemic sclerosis (scleroderma) is a complex, multisystem disease involving tissue fibrosis, immunological derangements and vascular abnormalities. Previous epidemiological studies provide compelling evidence that patients with scleroderma have an increased risk of cancer compared to the general population. Observations of a close temporal relationship between cancer diagnosis and scleroderma onset, and reports of cancer therapy halting scleroderma progression, suggest that scleroderma may be a paraneoplastic syndrome in some patients. In this proposal, the candidate will probe the temporal relationship between scleroderma and cancer, examine risk factors for cancer in scleroderma, and assess whether scleroderma autoantigen expression in tumors is associated with the immune response. This research will define patient subsets that may benefit from targeted malignancy screening, provide insight into mechanisms relevant in scleroderma pathogenesis, and offer the candidate an opportunity to build a strong clinical and translational research program in a mentored environment. The candidate has demonstrated a commitment to a career in academic rheumatology through her training in Johns Hopkins'Graduate Training Program in Clinical Investigation and her ability to initiate and complete investigations of clinically relevant questins in scleroderma. This Mentored Patient-Oriented Research Career Development Award will afford the candidate the opportunity to continue building on these skills, in part through planned coursework at the Johns Hopkins Bloomberg School of Public Health. The dedicated mentorship team, diverse clinical and research environment in the Division of Rheumatology, and resources of the School of Public Health are an ideal foundation for this mentored patient-oriented research career development award. The large team of mentors and collaborators for this proposal provide significant expertise in studying the epidemiology and basic immunologic underpinnings of scleroderma and cancer. In addition, the resources of the Johns Hopkins Scleroderma Center (JHSC);the large JHSC and Royal Free Hospital scleroderma databases of over 4800 subjects;the Bayview Biostatistics, Epidemiology and Data Management (BEAD) Core;the Johns Hopkins Division of Oncology;and the Rheumatic Diseases Research Core Center (RDRCC) are fully available to make this project a success.

Public Health Relevance

This research will probe the connection between cancer and an autoimmune disease called scleroderma. By identifying clinical and laboratory factors that are associated with an increased risk of cancer in scleroderma, this study may define a population of patients who would benefit from targeted cancer screening. This investigation will also provide insight into mechanisms of disease initiation that may be relevant for the study of autoimmune diseases in general.

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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Mancini, Marie
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Johns Hopkins University
Internal Medicine/Medicine
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United States
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Gourh, Pravitt; Remmers, Elaine F; Boyden, Steven E et al. (2018) Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans. Arthritis Rheumatol 70:1654-1660
Ogdie, Alexis; Sparks, Jeffrey A; Angeles-Han, Sheila T et al. (2018) Barriers and Facilitators of Mentoring for Trainees and Early Career Investigators in Rheumatology Research: Current State, Identification of Needs, and Road Map to an Inter-Institutional Adult Rheumatology Mentoring Program. Arthritis Care Res (Hoboken) 70:445-453
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Wu, Zhenke; Casciola-Rosen, Livia; Shah, Ami A et al. (2017) Estimating autoantibody signatures to detect autoimmune disease patient subsets. Biostatistics :
Shah, Ami A; Rosen, Antony; Hummers, Laura K et al. (2017) Evaluation of cancer-associated myositis and scleroderma autoantibodies in breast cancer patients without rheumatic disease. Clin Exp Rheumatol 35 Suppl 106:71-74
Shah, Ami A; Casciola-Rosen, Livia (2017) Mechanistic and clinical insights at the scleroderma-cancer interface. J Scleroderma Relat Disord 2:153-159

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