Molecular Markers for Progression of Pulmonary Fibrosis in Systemic Sclerosis

系统性硬化症肺纤维化进展的分子标志物

• 批准号: 8165452
• 负责人: Shervin Assassi
• 金额: $ 12.33万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8165452
• 关键词: Academic Medical Centers; Address; Applications Grants; Appointment; Area; Arthritis; Autoimmunity; Award; Bioethics; Bioinformatics; Biological Assay; Biological Markers; Biometry; Biostatistics Core; Blood Cells; Blood specimen; Cessation of life; Clinic; Clinical; Clinical Data; Clinical Research; Clinical Sciences; Clinical Trials Design; Collaborations; Complement; Complication; Connective Tissue Diseases; DNA Microarray Chip; Data; Data Analyses; Death Rate; Development; Development Plans; Disease; Disease Progression; Early Diagnosis; Educational Curriculum; Environment; Epidemiology; Evidence Based Medicine; Fibrosis; Funding; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genetic; Genomics; Goals; Grant; Health Sciences; Immune; Indolent; Institution; Interferons; Interstitial Lung Diseases; Knowledge; Laboratories; Lead; Lung; Lymphocyte; Master' s Degree; Measurement; Mentored Clinical Scientist Development Program; Mentors; Mentorship; Methodology; Microarray Analysis; Modality; Modeling; Molecular; Molecular Profiling; Monitor; Morbidity - disease rate; Outcome; Outcome Study; Patients; Pattern; Peer Review; Predictive Value; Principal Investigator; Progressive Disease; Prospective Studies; Proteomics; Publications; Publishing; Pulmonary Fibrosis; RNA; Research; Research Design; Research Infrastructure; Research Personnel; Research Project Grants; Research Training; Respiratory Failure; Rheum; Rheumatism; Rheumatology; SECTM1 gene; Sampling; Scientist; Scleroderma; Serum; Skin; Subgroup; Systemic Scleroderma; Technology; Texas; Therapeutic; Tissues; Training; Transcript; Translational Research; United States National Institutes of Health; Universities; Whole Blood; Work; Writing; base; career; career development; chemokine; clinical care; cohort; design; experience; high risk; improved; molecular marker; monocyte; mortality; novel; peripheral blood; professor; programs; prospective; pulmonary function; success

DESCRIPTION (provided by applicant): Title: Molecular Markers for Progression of Pulmonary Fibrosis in Systemic Sclerosis Candidate: Dr. Assassi is an Assistant Professor in the Division of Rheumatology and in the Center for Clinical Research and Evidence Based Medicine. He has recently completed a Master's Degree Program in Clinical Research. He was selected as one of just two CCTS-KL2 (K12) Scholars in 2009 at the University of Texas-Health Science Center at Houston (UTHSC-H). Dr. Maureen D. Mayes (primary mentor) and Dr. Filemon K. Tan (co-mentor) are his mentors in the ongoing KL2 Award. Under their guidance, the candidate has published the largest gene expression profiling study in systemic sclerosis (SSc) to date. Dr. Jon E. Tyson (co-mentor) mentored his Master's Thesis project, investigating the clinical predictors for progression of interstitial lung disease (ILD) in SSc. The results of this large prospective study have been recently published. These productive mentor-mentee relationships will build the basis for the success of this K23 proposal. Environment: UTHSC-H is one of the largest systemic sclerosis centers in the nation. This proposal takes advantage of the infrastructure provided by the ongoing NIH-funded prospective cohort of early SSc patients, the Genetics versus ENvironment In Scleroderma Outcome Study (GENISOS-PI: Dr. Mayes) and the active Scleroderma Clinic at our institution. The candidate's adjunct appointment in the Center for Clinical Research and Evidence Based Medicine provides access to a diverse group of investigators with expertise in biostatistics, bioinformatics and epidemiology. The candidate and his mentors also have ongoing collaborations with the CCTS Core Laboratories and Clinical Research Units at the UTHSC-H. The candidate has been able to co-author 21 peer-reviewed publications (17 in the last two years) in this supportive environment. Training Plan and Career Goals: The proposed four-year program provides intensive mentoring, didactic course work and independent scientific review. The didactic curriculum complements the candidate's prior training in the Master's program with courses in genomics and proteomics, longitudinal and Bayesian data analysis, bioethics and advanced grant writing. Candidate's research efforts are focused on combining high- throughput molecular data with sophisticated epidemiology and biostatistical approaches for development of predictive biomarkers in SSc. This proposal will establish candidate's independent area of expertise with a goal of applying for NIH R01 Award, focusing on identification of predictive biomarkers in rheumatic diseases and examination of their clinical usefulness in prospective studies. Proposed Research: SSc is associated with substantial morbidity and mortality. Pulmonary involvement is the primary cause of SSc-related death. Sequential measurements of pulmonary function in patients with SSc have shown remarkable variability in the progression of ILD, ranging from an indolent course to a rapidly progressive disease leading to respiratory failure and eventually death. Although ILD is one of the most important determinants of disease in SSc, the routinely obtained demographic and clinical data are inadequate to predict the course of this devastating disease complication. Gene expression profiling with microarrays allows the simultaneous assessment of thousands of transcripts in a given tissue. Our previous studies indicate that SSc patients can be subclassified at the molecular level based on presence of an Interferon (IFN) gene expression pattern. The objective of the current proposal is to build multivariate models with gene expression profiling and serum chemokine data that will have greater predictive value for the course of ILD over the currently known parameters. We hypothesize that microarray gene expression profiling and multiplex chemokine assays will improve our currently inadequate ability to predict the course of ILD. We will identify peripheral blood cell and skin gene expression patterns that can predict the course of ILD. Then we will examine the independent predictive significance of these classifier transcripts in a multivariate model after inclusion of other known predictors. We also will investigate the interplay between immune dysregulations and fibrosis in SSc by comparison of gene expression profiles present in the concomitantly collected peripheral blood and skin samples. Several serum chemokines correlating with the IFN gene expression signature have been identified. These chemokines correlate with disease activity in other connective tissue disease. In this proposal, we will examine whether these IFN inducible chemokines also correlate with progression of SSc-ILD in the GENISOS cohort. The proposed novel translational and analytic approaches can lead to methodological advances in the field of autoimmunity and can address a significant knowledge gap in SSc clinical care and clinical trial design. Furthermore, the accompanying mentoring and course work will prepare Dr. Assassi to become an independent and productive clinician scientist and a leader in rigorously designed and conducted translational research in rheumatic diseases. PUBLIC HEALTH RELEVANCE: Interstitial lung disease is a major complication of systemic sclerosis (scleroderma) leading to increased death rates among patients with this disease. We will use advanced technology to identify molecules that predict the course of interstitial lung disease. This can lead to early detection of high risk systemic sclerosis patients who would benefit from more intensive monitoring and treatment.

描述（由申请人提供）： 标题：系统性硬化症肺纤维化进展的分子标记 候选人：Assassi 博士是风湿病科和临床研究和循证医学中心的助理教授。他最近完成了临床研究硕士学位课程。 2009 年，他被选为德克萨斯大学休斯顿健康科学中心 (UTHSC-H) 仅有的两名 CCTS-KL2 (K12) 学者之一。 Maureen D. Mayes 博士（主要导师）和 Filemon K. Tan 博士（共同导师）是他在正在进行的 KL2 奖中的导师。在他们的指导下，该候选人发表了迄今为止最大的系统性硬化症（SSc）基因表达谱研究。 Jon E. Tyson 博士（联合导师）指导了他的硕士论文项目，研究 SSc 间质性肺病 (ILD) 进展的临床预测因素。这项大型前瞻性研究的结果最近已发表。 这些富有成效的导师与学员关系将为 K23 提案的成功奠定基础。 环境：UTHSC-H 是美国最大的系统性硬化症中心之一。该提案利用了由 NIH 资助的早期 SSc 患者前瞻性队列、硬皮病结果中的遗传学与环境研究（GENISOS-PI：Mayes 博士）和我们机构活跃的硬皮病诊所提供的基础设施。候选人在临床研究和循证医学中心的兼职任命为该候选人提供了接触具有生物统计学、生物信息学和流行病学专业知识的多元化研究人员群体的机会。候选人和他的导师还与 UTHSC-H 的 CCTS 核心实验室和临床研究单位持续合作。在这种支持性环境中，候选人已能够共同撰写 21 篇同行评审出版物（过去两年 17 篇）。 培训计划和职业目标：拟议的四年计划提供强化指导、教学课程工作和独立的科学审查。教学课程补充了候选人之前在硕士课程中接受的培训，包括基因组学和蛋白质组学、纵向和贝叶斯数据分析、生物伦理学和高级资助写作课程。候选人的研究工作重点是将高通量分子数据与复杂的流行病学和生物统计学方法相结合，以开发 SSc 的预测生物标志物。该提案将建立候选人的独立专业领域，目标是申请 NIH R01 奖，重点是识别风湿性疾病的预测生物标志物并检查其在前瞻性研究中的临床实用性。 拟议的研究：SSc 与大量的发病率和死亡率相关。肺部受累是 SSc 相关死亡的主要原因。对 SSc 患者肺功能的连续测量显示 ILD 进展存在显着差异，从惰性病程到导致呼吸衰竭并最终死亡的快速进展疾病。尽管 ILD 是 SSc 疾病最重要的决定因素之一，但常规获得的人口统计和临床数据不足以预测这种破坏性疾病并发症的病程。 使用微阵列进行基因表达谱分析可以同时评估给定组织中的数千个转录本。我们之前的研究表明，SSc 患者可以根据干扰素 (IFN) 基因表达模式在分子水平上进行细分。 当前提案的目标是建立具有基因表达谱和血清趋化因子数据的多变量模型，与目前已知的参数相比，该模型对 ILD 的病程具有更大的预测价值。我们假设微阵列基因表达谱和多重趋化因子测定将改善我们目前预测 ILD 病程的能力不足。 我们将确定可以预测 ILD 病程的外周血细胞和皮肤基因表达模式。 然后，我们将在包含其他已知预测因子后，在多变量模型中检查这些分类器转录本的独立预测意义。我们还将通过比较同时收集的外周血和皮肤样本中存在的基因表达谱来研究 SSc 中免疫失调和纤维化之间的相互作用。已鉴定出几种与 IFN 基因表达特征相关的血清趋化因子。这些趋化因子与其他结缔组织疾病的疾病活动相关。在本提案中，我们将研究这些 IFN 诱导趋化因子是否也与 GENISOS 队列中 SSc-ILD 的进展相关。所提出的新颖的转化和分析方法可以导致自身免疫领域的方法学进步，并可以解决 SSc 临床护理和临床试验设计中的重大知识差距。此外，伴随的指导和课程工作将使阿萨西博士成为一名独立且富有成效的临床科学家，以及严格设计和进行风湿性疾病转化研究的领导者。 公共卫生相关性：间质性肺疾病是系统性硬化症（硬皮病）的主要并发症，导致该疾病患者的死亡率增加。我们将使用先进技术来识别预测间质性肺病病程的分子。这可以导致早期发现高风险系统性硬化症患者，他们将受益于更深入的监测和治疗。