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: 8702083
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702083
• 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; 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; cohort; data management; design; experience; 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; 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（由申请人提供）：Hinchcliff博士是西北大学流变学医学助理教授，也是西北硬皮病项目的副临床主任。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，在她的导师的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储存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（建设跨学科研究职业妇女健康）在此期间，她产生了令人兴奋的初步基因组学数据，为目前的建议。Hinchcliff博士现在寻求获得设计和进行创新临床研究的经验和专业知识，包括高通量方法（遗传学，基因组学，蛋白质组学，代谢组学等）作为分子SSc生物标志物，以更好地了解疾病的发病机制，以及疾病过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。一些患者的疾病进展，需要用潜在的毒性药物治疗，而许多患者的疾病稳定或消退，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分类系统是预测疾病过程或治疗反应的不可靠的生物标志物。最近，一种新的SSc分类的基础上，在皮肤中的基因表达和所谓的“内在子集分析”已被确定和验证在多个独立的患者队列。目前提案的总体目标是评估三种基因表达的能力 在初步研究中确定的皮肤特征，包括内在子集分配，以预测对霉酚酸酯（一种常用处方治疗）的治疗反应。为了实现目标招募，并允许Hinchcliff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：学术环境是理想的拟议项目以及职业发展。必要的基础设施和丰富的学术环境存在，以支持从指导到独立的成功过渡。这些包括盛大的回合，期刊俱乐部和由皮肤科，医学，风湿病学，NU遗传医学中心等主办的广泛的每周会议，以下四个资源直接关系到博士Hinchcliff的职业发展目标：1）一个强大的K23导师委员会由三个NIH资助的研究人员（博士罗兰W。Chang，John Varga和Michael Whitfield）; 2）以SSc疾病为重点的患者登记处和生物储存库，包含>600例SSc患者的标本和临床数据（每年>150名新患者）; 3）流变学方法学/数据管理核心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）新研究者职业提升研讨会旨在专门解决年轻教师的需求和关注，以及DOM教师事务办公室赞助的手稿冲刺和资助写作每周研讨会，帮助候选人发表五篇原创研究论文并获得资助支持。研究职业发展计划的关键要素包括与Varga博士和Chang博士每周一次的导师会议，以及与Whitfield博士定期安排的电话会议，参加研究会议和正式课程工作。Hinchcliff博士将与几个跨学科研究小组进行互动，并向他们展示她的研究计划和研究结果，这些小组由具有专业知识和对Hinchcliff博士的研究感兴趣的成员组成。将在颁奖期间完成的教学课程工作 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。总结：Hinchcliff博士的长期职业目标是成为一名SSc介入流行病学家，他设计和执行创新的临床研究，利用现有的和最先进的研究工具对患者进行表型分析，识别新的生物标志物，了解疾病机制，并评估对新疗法的治疗反应。在短期内，她将完成提案中概述的实验，提交研究结果供发表，并继续发展大型复杂数据集分析方面的专业知识，以及高通量平台与临床数据的整合。从长远来看，Hinchcliff博士将成为SSc系统生物学的领导者。她将利用新的分子靶点的鉴定和疾病发病机制的新兴思想，设计和进行临床研究，以测试这些理论，最终目标是为SSc患者制定个性化的治疗策略。