Predictive Ability of Gene Expression Signatures In Skin as SSc Biomarkers

简介（由申请人提供）：Hinchcliff博士是西北大学风湿病医学助理教授，西北硬皮病项目临床副主任。她在系统性硬化症（SSc）患者的诊断和治疗方面有七年的经验，在导师的SSc研究实验室完成了两年的培训，在建立西北硬皮病项目患者登记和生物库方面发挥了主导作用，为以患者为导向的研究奠定了基础，完成了临床研究硕士学位（2008-10）。并被授予机构K12（建立妇女健康跨学科研究事业），在此期间，她为当前的提案提供了令人兴奋的初步基因组学数据。Hinchcliff博士现在寻求在设计和开展创新临床研究方面获得经验和专业知识，包括高通量方法（遗传，基因组，蛋白质组学，代谢组学等）作为分子SSc生物标志物，以更好地了解疾病发病机制，疾病病程和治疗反应的异质性，并最终确定新的治疗靶点。研究计划：Hinchcliff博士直接观察SSc表型异质性。一些患者病情进展，需要使用潜在毒性药物治疗，而许多患者病情稳定或退行性，不需要积极治疗。目前基于血清自身抗体和皮肤纤维化程度的SSc分类系统是预测病程或治疗反应的不可靠的生物标志物。最近，一种新的基于皮肤基因表达的SSc分类，被称为“内在亚群分析”，已经在多个独立的患者队列中被确定并验证。当前提案的总体目标是评估三个基因表达的能力

DESCRIPTION (provided by applicant): 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.