Dr. Hinchcliff is an Assistant Professor of Medicine in Rheumatology at Northwestern University, and Associate Clinical Director of the Northwestern Scleroderma Program. She has seven years of experience in the diagnosis and treatment of patients with systemic sclerosis (SSc), has completed two years of training in her mentor's SSc research laboratory, played a lead role in establishing the Northwestern Scleroderma Program Patient Registry and Biorepository to lay a foundation for a career in patient-oriented research, completed a Master's degree in Clinical Investigation (2008-10), and was awarded an Institutional K12 (Building Interdisciplinary Research Career in Women's Health) during which time she generated exciting preliminary genomics data for the current proposal. Dr. Hinchcliff now seeks to gain experience and expertise in designing and conducting innovative clinical investigations that include high-throughput approaches (genetic, genomic, proteomic, metabolomic etc.) as molecular SSc biomarkers to better understand disease pathogenesis, and heterogeneity in disease course and treatment response, and to ultimately identify new therapeutic targets. Research Plan: Dr. Hinchcliff observes SSc phenotypic heterogeneity first-hand. Some patients have progressive disease that warrants treatment with potentially toxic medications, while many patients have stable or regressive disease that does not warrant aggressive treatment. Current SSc classification systems based upon serum autoantibodies and extent of skin fibrosis are unreliable biomarkers to predict disease course or treatment response. Recently, a new SSc classification based upon gene expression in skin and termed 'intrinsic subset analysis'has been identified and validated in multiple independent patient cohorts. The overall goal of the current proposal is to assess the ability of three gene expression signatures in skin that were identified during pilot studies, including intrinsic subset assignment to predict treatment response to mycophenolate mofetil, a commonly prescribed treatment. To achieve targeted enrollment and to allow Dr. Hinchcliff to gain experience conducting multicenter studies, patients will be recruited from three large academic scleroderma programs. Environment: The academic environment is ideal for the proposed projects as well as for career development. Necessary infrastructure and a rich academic milieu exist to support the successful transition from mentored to independence. These include grand rounds, journal clubs and a broad array of weekly conferences hosted by dermatology, medicine, rheumatology, the NU Center for Genetic Medicine, etc. The following four resources are directly related to Dr. Hinchcliff's goals for career development: 1) a strong K23 mentorship committee composed of three NIH-funded investigators (Drs. Rowland W. Chang, John Varga, and Michael Whitfield);2) an SSc disease-focused patient registry and biorepository that contains specimens and clinical data for >600 patients with SSc (>150 new patients annually);3) the Multidisciplinary Clinical Research Center in Rheumatology Methodology/Data Management Core that provides methodological support for study design and data collection and analysis;4) the Department of Medicine (DOM) New Investigator Career Enhancement Seminars designed to specifically address the needs and concerns of young faculty, and DOM Office of Faculty Affairs-sponsored manuscript sprints and grant writing weekly seminars that have helped the Candidate publish five original research papers and obtain grant support. Key elements of the research career development plan include weekly mentorship meetings with Drs. Varga and Chang and regularly scheduled teleconferences with Dr. Whitfield, attendance at research meetings and formal course work. Dr. Hinchcliff will interact with and present her research plans and study results to several interdisciplinary research groups comprised of members with expertise and interest in Dr. Hinchcliff's research. Didactic course work that will be completed during the award includes: Team Science, Bioinformatics, Advanced Epidemiology and Advanced Biostatistics. Summary: Dr. Hinchcliff's long-term career goal is to become an SSc interventional epidemiologist who designs and executes innovative clinical investigations that utilize established and state-of-the-art research tools to phenotype patients, identify novel biomarkers, understand disease mechanism, and assess treatment response to new therapies. In the short-term, she will complete the experiments outlined in the proposal, submit study results for publication, and continue to develop expertise in the analysis of large and complex data sets, and integration of high-throughput platforms with clinical data. In the long-term, Dr. Hinchcliff wll become a leader in the systems biology of SSc. She will capitalize upon identification of new molecular targets and emerging ideas of disease pathogenesis and design and conduct clinical investigations to test these theories with the ultimate goal of developing personalized treatment strategies for patients with SSc.

Public Health Relevance

There are many therapies including mycophenolate mofetil (Cellcept) for the treatment of systemic sclerosis skin disease, but response is heterogeneous and current patient classification systems are not helpful in aiding treatment decisions. A new classification system called 'intrinsic subset assignment'based gene expression in skin has been validated in SSc patients, mapped to animal models of disease, and found to be associated with mycophenolate mofetil response. The experiments outlined in this proposal will determine whether gene expression signatures in skin, including intrinsic subset assignment, can predict mycophenolate response.

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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Tseng, Hung H
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Northwestern University at Chicago
Internal Medicine/Medicine
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United States
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Lee, Daniel C; Hinchcliff, Monique E; Sarnari, Roberto et al. (2018) Diffuse cardiac fibrosis quantification in early systemic sclerosis by magnetic resonance imaging and correlation with skin fibrosis. J Scleroderma Relat Disord 3:159-169
Stern, E K; Carlson, D A; Falmagne, S et al. (2018) Abnormal esophageal acid exposure on high-dose proton pump inhibitor therapy is common in systemic sclerosis patients. Neurogastroenterol Motil 30:
Showalter, Kimberly; Hoffmann, Aileen; Rouleau, Gerald et al. (2018) Performance of Forced Vital Capacity and Lung Diffusion Cutpoints for Associated Radiographic Interstitial Lung Disease in Systemic Sclerosis. J Rheumatol 45:1572-1576
Taroni, Jaclyn N; Greene, Casey S; Martyanov, Viktor et al. (2017) A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis. Genome Med 9:27
Lammi, Matthew R; Mathai, Stephen C; Saketkoo, Lesley Ann et al. (2016) Association Between Initial Oral Therapy and Outcomes in Systemic Sclerosis-Related Pulmonary Arterial Hypertension. Arthritis Rheumatol 68:740-8
Kimmel, J N; Carlson, D A; Hinchcliff, M et al. (2016) The association between systemic sclerosis disease manifestations and esophageal high-resolution manometry parameters. Neurogastroenterol Motil 28:1157-65
Ziemek, Jessica; Man, Ada; Hinchcliff, Monique et al. (2016) The relationship between skin symptoms and the scleroderma modification of the health assessment questionnaire, the modified Rodnan skin score, and skin pathology in patients with systemic sclerosis. Rheumatology (Oxford) 55:911-7
Tashkin, Donald P; Roth, Michael D; Clements, Philip J et al. (2016) Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med 4:708-719
Valenzuela, Antonia; Baron, Murray; Canadian Scleroderma Research Group et al. (2016) Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: A Scleroderma Clinical Trials Consortium study. Semin Arthritis Rheum 46:344-349
Hinchcliff, Monique E; Lomasney, Jon; Johnson, Julie A et al. (2016) Fulminant capillary leak syndrome in a patient with systemic sclerosis treated with imatinib mesylate. Rheumatology (Oxford) 55:1916-8

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