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: 8318622
• 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/8318622
• 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; 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; 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; didactic education; 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.

描述（由申请人提供）：标题：全身性硬化症候选肺纤维化进展的分子标记：Assassi博士是风湿病学系的助理教授以及临床研究和基于证据的医学中心。他最近完成了临床研究硕士学位课程。他于2009年在休斯敦（UTHSC-H）的德克萨斯大学医疗科学中心（UTHSC-H）中被选为仅有的两个CCTS-KL2（K12）学者之一。 Maureen D. Mayes博士（主要导师）和Filemon K. Tan博士（Co-Incertor）是他正在进行的KL2奖的导师。在他们的指导下，候选人发表了迄今为止在系统性硬化症（SSC）中最大的基因表达分析研究。乔恩·泰森（Jon E. Tyson）博士（同事）指导了他的硕士论文项目，研究了SSC中间质性肺疾病（ILD）进展的临床预测因子。这项大型前瞻性研究的结果最近发表了。 这些富有成效的导师关系将为这项K23提案的成功提供基础。 环境：UTHSC-H是美国最大的系统性硬化症中心之一。该提案利用了正在进行的NIH资助的早期SSC患者的前瞻性队列，硬皮病结局研究中的遗传学与环境（Genisos-Pi：Mayes博士）和我们机构的主动硬皮病诊所提供的基础设施。候选人在临床研究和证据医学中心的兼职任命提供了对具有生物统计学，生物信息学和流行病学专业知识的各种研究人员的访问权。候选人和他的导师还与UTHSC-H的CCTS核心实验室和临床研究部门进行了持续的合作。该候选人能够在这种支持性的环境中合着21个同行评审的出版物（过去两年中的17个）。 培训计划和职业目标：拟议的四年计划提供密集的指导，教学课程工作和独立的科学审查。教学课程通过基因组学和蛋白质组学，纵向和贝叶斯数据分析，生物伦理学和先进的赠款写作的课程，对候选人的先前培训进行了补充。候选人的研究工作集中在将高吞吐量分子数据与复杂的流行病学和生物统计学方法结合在一起，用于开发SSC中的预测性生物标志物。该提案将建立候选人的独立专业知识领域，目的是申请NIH R01奖，重点是鉴定风湿病疾病中的预测生物标志物，并在前瞻性研究中检查其临床实用性。 拟议的研究：SSC与大量发病率和死亡率有关。肺部受累是与SSC相关死亡的主要原因。 SSC患者肺功能的顺序测量在ILD的进展方面表现出显着的差异，从顽强的病程到快速进行性疾病，导致呼吸衰竭，最终导致死亡。尽管ILD是SSC疾病最重要的决定因素之一，但通常获得的人口统计学和临床​​数据不足以预测这种毁灭性疾病并发症的过程。 用微阵列进行基因表达分析允许同时评估给定组织中数千个转录本。我们先前的研究表明，可以根据干扰素（IFN）基因表达模式在分子水平上进行SSC患者。 当前建议的目的是建立具有基因表达分析和血清趋化因子数据的多元模型，这些模型将对ILD在当前已知的参数上具有更大的预测价值。我们假设微阵列基因表达分析和多重趋化因子测定将提高我们当前预测ILD过程的能力。 我们将确定可以预测ILD过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，在多元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，研究SSC中免疫失调与纤维化之间的相互作用。已经鉴定出与IFN基因表达特征相关的几种血清趋化因子。这些趋化因子与其他结缔组织疾病中的疾病活性相关。在此提案中，我们将检查这些IFN诱导趋化因子是否也与Genisos队列中的SSC-ILD的进展相关。拟议的新型翻译和分析方法可以导致自身免疫领域的方法论进步，并可以解决SSC临床护理和临床试验设计中的显着知识差距。此外，随附的指导和课程工作将使Assassi博士成为一名独立，生产性的临床医生，并在严格设计和进行风湿病的转化研究领域。