Predictive Ability of Gene Expression Signatures In Skin as SSc Biomarkers

皮肤基因表达特征作为 SSc 生物标志物的预测能力

• 批准号: 8886940
• 负责人: MONIQUE Evangeline HINCHCLIFF
• 金额: $ 13万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886940
• 关键词: Address; Aftercare; Animal Disease Models; Autoantibodies; Autoimmune Diseases; Award; Bioinformatics; Biological Markers; Biometry; Biopsy; Cellcept; Cells; Classification; Clinical; Clinical Course of Disease; Clinical Data; Clinical Research; Clinical Trials; Complement; Complex; DNA Microarray Chip; Data; Data Analyses; Data Collection; Data Set; Databases; Dermatology; Development; Development Plans; Diagnosis; Disease; Elements; Enrollment; Environment; Epidemiologist; Epidemiology; Etiology; Faculty; Fibrosis; Fostering; Foundations; Funding; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Medicine; Genomics; Goals; Grant; Health; Heart; Heterogeneity; Inflammatory; Innovative Therapy; Institutional National Research Service Award; Interdisciplinary Study; Journals; Laboratories; Laboratory Research; Lead; Learning; Lung; Manuscripts; Maps; Master' s Degree; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methodology; Methods; Microarray Analysis; Molecular; Molecular Profiling; Molecular Target; Multicenter Studies; Mycophenolate; Observational Study; Outcome; Paper; Pathogenesis; Pathway interactions; Patient Outcomes Assessments; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Pilot Projects; Play; Progressive Disease; Proteomics; Publications; Publishing; Recruitment Activity; Research; Research Design; Research Infrastructure; Research Personnel; Resources; Rheumatology; Role; SECTM1 gene; Schedule; Science; Scientist; Scleroderma; Serum; Skin; Specimen; System; Systemic Scleroderma; Systems Biology; Teleconferences; Testing; Time; Training; United States National Institutes of Health; Universities; Validation; Women' s Health; Work; Writing; base; biobank; career; career development; clinical investigation; cohort; data management; design; experience; genetic approach; improved; innovation; insight; interest; lymphocyte proliferation; meetings; member; metabolomics; multidisciplinary; mycophenolate mofetil; new technology; new therapeutic target; novel; open label; patient oriented research; patient registry; personalized medicine; professor; programs; prospective; research study; response; skills; skin disorder; standard of care; symposium; theories; tool; treatment response; treatment strategy

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.

描述(申请人提供)：欣克利夫博士是西北大学风湿病医学助理教授，西北硬皮病项目副临床主任。她在诊断和治疗系统性硬化症(SSC)患者方面有七年的经验，在导师的SSC研究实验室完成了两年的培训，在建立西北硬皮病计划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职业生涯的基础，完成了临床调查硕士学位(2008-10)，并获得了机构K12(建立妇女健康跨学科研究生涯)，在此期间，她为当前的提案生成了令人兴奋的初步基因组数据。欣克利夫博士现在寻求在设计和进行创新的临床研究方面获得经验和专业知识，其中包括高通量方法(遗传、基因组、蛋白质组、代谢组学等)。作为SSC的分子生物标记物，可以更好地了解疾病的发病机制，以及病程和治疗反应的异质性，最终发现新的治疗靶点。研究计划：Hinchcliff博士直接观察SSC表型的异质性。一些患者患有进展性疾病，需要使用潜在的毒性药物进行治疗，而许多患者患有稳定或退化的疾病，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分类系统不能可靠地预测病程或治疗反应。最近，一种新的基于皮肤中基因表达的SSC分类被识别并在多个独立的患者队列中得到验证。目前提案的总体目标是评估三个基因的表达能力 在试点研究中确定的皮肤特征，包括预测霉酚酸酯治疗反应的内在亚组分配，这是一种常见的处方药。为了实现有针对性的登记，并让欣克利夫博士获得进行多中心研究的经验，将从三个大型学术硬皮病项目中招募患者。环境：学术环境对于所提议的项目以及职业发展来说都是理想的。存在必要的基础设施和丰富的学术环境，以支持从有导师到独立的成功过渡。这些活动包括由皮肤科、医学、风湿科、国立大学遗传医学中心等主办的大型会议、期刊俱乐部和广泛的每周会议。以下四个资源与欣奇克利夫博士的职业发展目标直接相关：1)由三名NIH资助的研究人员(罗兰·W·张博士、约翰·瓦尔加博士和迈克尔·惠特菲尔德博士)组成的强大的K23指导委员会；2)以SSC疾病为重点的患者登记和生物库，其中包含&GT的标本和临床数据；600名SSC患者(&GT；每年150名新患者)；3)风湿学方法论/数据管理核心领域的多学科临床研究中心，为研究设计和数据收集和分析提供方法学支持；4)医学系(DOM)新研究员职业发展研讨会，专门针对年轻教师的需求和关切，以及DOM教务处赞助的手稿冲刺和每周拨款写作研讨会，帮助候选人发表五篇原创研究论文并获得拨款支持。研究职业发展计划的关键要素包括每周与瓦尔加博士和张博士举行的指导会议，定期安排与惠特菲尔德博士的电话会议，参加研究会议和正式的课程工作。欣奇克利夫博士将与几个跨学科研究小组互动，并向他们展示她的研究计划和研究结果，这些小组由对欣克利夫博士的研究具有专业知识和兴趣的成员组成。授课工作将在颁奖期间完成 包括：团队科学、生物信息学、高级流行病学和高级生物统计学。摘要：欣克利夫博士的长期职业目标是成为一名SSC介入流行病学家，设计和执行创新的临床研究，利用现有和最先进的研究工具对患者进行表型分析，识别新的生物标记物，了解疾病机制，并评估对新疗法的治疗反应。短期内，她将完成提案中概述的实验，提交研究结果以供发表，并继续发展大型复杂数据集分析以及高通量平台与临床数据整合方面的专业知识。从长远来看，欣奇克利夫博士将成为SSC系统生物学领域的领导者。她将利用识别新的分子靶点和疾病发病机制的新想法，并设计和进行临床研究来测试这些理论，最终目标是为SSC患者开发个性化治疗策略。

项目成果

Association Between Initial Oral Therapy and Outcomes in Systemic Sclerosis-Related Pulmonary Arterial Hypertension.

• DOI: 10.1002/art.39478
• 发表时间: 2016-03
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Lammi MR;Mathai SC;Saketkoo LA;Domsic RT;Bojanowski C;Furst DE;Steen VD;Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Investigators
• 通讯作者: Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Investigators

Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: A Scleroderma Clinical Trials Consortium study.

• DOI: 10.1016/j.semarthrit.2016.05.008
• 发表时间: 2016-12
• 期刊: Seminars in arthritis and rheumatism
• 影响因子: 5
• 作者: Valenzuela A;Baron M;Canadian Scleroderma Research Group;Herrick AL;Proudman S;Stevens W;Australian Scleroderma Interest Group;Rodriguez-Reyna TS;Vacca A;Medsger TA Jr;Hinchcliff M;Hsu V;Wu JY;Fiorentino D;Chung L
• 通讯作者: Chung L

Fulminant capillary leak syndrome in a patient with systemic sclerosis treated with imatinib mesylate.

接受甲磺酸伊马替尼治疗的系统性硬化症患者发生暴发性毛细血管渗漏综合征。

• DOI: 10.1093/rheumatology/kew245
• 发表时间: 2016
• 期刊: Rheumatology (Oxford, England)
• 作者: Hinchcliff,MoniqueE;Lomasney,Jon;Johnson,JulieA;Varga,John
• 通讯作者: Varga,John