Molecular Markers for Progression of Pulmonary Fibrosis in Systemic Sclerosis

描述（由申请人提供）：标题：系统性硬化症中肺纤维化进展的分子标志物候选人：刺客博士是临床研究和循证医学中心风湿病学部门的助理教授。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（联合导师）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最大的系统性硬化症（SSc）基因表达谱研究。Jon E. Tyson博士（共同导师）指导他的硕士论文项目，研究SSc中间质性肺疾病（ILD）进展的临床预测因素。这项大型前瞻性研究的结果最近发表了。这些富有成效的师徒关系将为K23提案的成功奠定基础。环境：UTHSC-H是全国最大的系统性硬化症中心之一。该建议利用了正在进行的nih资助的早期SSc患者前瞻性队列、硬皮病结局研究中的遗传与环境（GENISOS-PI: Dr. Mayes）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样化研究人员的机会。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进行了持续的合作。在这种支持的环境下，候选人已经能够共同撰写21篇同行评审的出版物（过去两年中有17篇）。培训计划和职业目标：建议的四年计划提供密集的指导，教学课程和独立的科学审查。教学课程补充了候选人先前在硕士课程中的培训，包括基因组学和蛋白质组学，纵向和贝叶斯数据分析，生物伦理学和高级拨款写作。候选人的研究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的预测性生物标志物。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性生物标志物，并检查其在前瞻性研究中的临床用途。拟议研究：SSc与大量发病率和死亡率相关。肺部受累是ssc相关死亡的主要原因。SSc患者肺功能的连续测量显示，ILD的进展具有显著的可变性，从无痛过程到快速进展的疾病导致呼吸衰竭并最终死亡。虽然ILD是SSc中最重要的疾病决定因素之一，但常规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病程。基因表达谱与微阵列允许同时评估数以千计的转录本在一个给定的组织。我们之前的研究表明，SSc患者可以根据干扰素（IFN）基因表达模式的存在在分子水平上进行亚分类。当前建议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，这些模型将比目前已知的参数对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种趋化因子分析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。几种与IFN基因表达特征相关的血清趋化因子已经被确定。这些趋化因子与其他结缔组织疾病的疾病活动相关。在这项提议中，我们将研究这些IFN诱导的趋化因子是否也与GENISOS队列中SSc-ILD的进展相关。提出的新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方面的重大知识差距。此外，伴随的指导和课程工作将使阿西博士成为一名独立和富有成效的临床医生科学家，并在严格设计和实施风湿病转化研究方面成为领导者。

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.