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博士是西北大学风湿病学医学助理教授，西北硬皮病计划的副临床主任。她在全身性硬化症患者（SSC）的诊断和治疗方面拥有七年的经验，已经完成了在导师的SSC研究实验室的两年培训，在建立西北硬皮病计划的患者登记册和生物工作人员中发挥了领先作用，为患者的研究颁发了一项奖项2的构建，并（2008-10）（2008-10）（（2008-10），妇女健康的跨学科研究职业）在此期间，她为当前的提案生成了令人兴奋的初步基因组学数据。 Hinchcliff博士现在试图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，蛋白质组学，代谢组学等）作为分子SSC生物标志物，以更好地了解疾病病原体，以及疾病过程中的异质性和治疗反应，以确定新的目标，并确定新的目标。研究计划：Hinchcliff博士第一手观察SSC表型异质性。一些患者患有进行性疾病，可以用潜在的有毒药物治疗，而许多患者患有稳定或回归性疾病，不保留侵略性治疗。当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病程或治疗反应的不可靠的生物标志物。最近，已经在多个独立的患者同类中鉴定出来并验证了基于皮肤中基因表达并称为“内在子集分析”的新的SSC分类。当前建议的总体目标是评估三个基因表达的能力 试点研究期间鉴定出的皮肤的特征，包括固有的子集分配，以预测对霉酚酸酯莫菲蒂尔的治疗反应，这是一种通常处方的治疗。为了获得有针对性的入学率，并允许Hinchcliff博士获得进行多中心研究的经验，将从三个大型的学术硬皮病计划中招募患者。环境：学术环境非常适合拟议的项目以及职业发展。存在必要的基础设施和丰富的学术环境，以支持从指导到独立性的成功过渡。其中包括大巡回赛，期刊俱乐部以及由皮肤病学，医学，风湿病，NU遗传医学中心等举办的各种每周一次的会议。以下四个资源与Hinchcliff博士的职业发展目标直接相关：1）一个强大的K23 Mentorship委员会由三个NIH资助的研究员组成，由三个NIH资助的研究员组成。 2）以SSC疾病为中心的患者登记处和生物座位，其中包含> 600名SSC患者的标本和临床数据（每年> 150名新患者）； 3）风湿病方法/数据管理核心的多学科临床研究中心，为研究设计以及数据收集和分析提供方法学支持； 4）医学系（DOM）新调查员职业增强研讨会旨在特别满足年轻教职员工的需求和关注，以及DOM事务事务赞助的手稿Sprints和Grant撰写的每周撰写每周撰写每周的研讨会，这些研讨会帮助候选人出版了五份原创研究论文并获得赠款支持。研究职业发展计划的关键要素包括与DRS的每周指导会议。 Varga和Chang以及惠特菲尔德博士定期安排了电视会议，参加了研究会议和正式课程工作。 Hinchcliff博士将与她的研究计划互动并介绍她的研究计划，并向几个跨学科研究小组组成，包括对Hinchcliff博士的研究的专业知识和兴趣组成的成员。奖励期间将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。摘要：Hinchcliff博士的长期职业目标是成为SSC介入的流行病学家，他设计和执行创新的临床研究，这些研究利用既定的，最先进的研究工具来识别表型患者，识别新型的生物标志物，了解疾病机制，了解对新疗法的治疗反应。在短期内，她将完成该提案中概述的实验，提交研究结果以发表，并继续在分析大型和复杂数据集的分析中发展专业知识，并将高通量平台与临床数据集成。从长远来看，Hinchcliff博士成为SSC系统生物学的领导者。她将利用鉴定新的分子靶标和疾病发病机理的新兴思想，并进行临床研究以测试这些理论，最终目标是为SSC患者制定个性化治疗策略。