Rheumatoid Arthritis Patients at Risk for Interstitial Lung Disease

这份申请是为乔伊斯·S博士申请的K23奖。李，一个助理教授在大学的 科罗拉多（CU）丹佛。职业目标：这个k23奖将促进以下目标：（1）了解 遗传和基因组流行病学在间质性肺病（ILD）领域的应用;（2）获得 大数据分析计算方法的知识;（3）开发生物标志物检测培训， 发展亚临床疾病状态;（4）进行临床和转化研究， 了解亚临床类风湿性关节炎相关ILD（RA-ILD）;（5）实现长期职业生涯 目标是成为ILD领域的独立临床和转化研究者。 指导：为了实现这些目标，李博士组建了一个由大卫博士组成的指导团队。 Schwartz（主要导师），ILD领域国际公认的科学家; Michael Holers博士（共同导师） 导师），国际公认的早期RA免疫学研究专家;和一项研究 咨询委员会，包括塔莎芬格林博士，一位专家统计遗传学家和遗传学家， 流行病学家和内容专家，包括凯文迪恩博士和吉尔诺里斯博士。培训与环境： 她已经构建了一个严格的职业发展计划，包括具体的课程，高影响力 研讨会和指导，以CU为中心，提供基础设施，资源和合作者 高影响力的临床研究所需的。 研究目的：本研究提案的总体目标是确定临床和 亚临床RA-ILD的分子/遗传表型。与健康的关系：RA-ILD死亡 尽管RA死亡率总体下降，但仍在增加。亚临床RA-ILD的早期检测将识别患者 具有较低的肺部疾病负担，潜在的更可挽救的肺，并可能揭示新的分子靶点 用于在这种进行性疾病的亚临床和/或早期临床阶段有效的干预。 依据：初步数据证明了RA-ILD与 特发性肺纤维化（IPF）。该提案利用了在 了解IPF的确定和亚临床形式。假设：有RA-ILD和IPF风险的患者 都有共同的临床遗传和生物学风险因素目的：本研究提案将定义 表型和估计亚临床RA-ILD的患病率（目的1），测试MUC 5 B变异体在 亚临床RA-ILD（目标2A），并推导和验证亚临床RA-ILD中的生物标志物谱（目标2B）。 方法：为了解决这一假设并实现这些目标，将入组400例RA患者， 使用高分辨率计算机断层扫描识别ILD异常。这些资料 开发一种稳健的风险预测算法，以识别临床环境中ILD风险最高的RA患者。 使用该队列，将研究与亚临床RA-ILD相关的遗传和生物学因素。

This application is for a K23 award for Dr. Joyce S. Lee, an Assistant Professor at the University of Colorado (CU) Denver. Career Goals: This k23 award will facilitate the following goals: (1) to understand the application of genetic and genomic epidemiology in the field of interstitial lung disease (ILD); (2) to gain knowledge in computational approaches to big data analysis; (3) to develop training in biomarker testing and development in subclinical disease states; (4) to conduct clinical and translational investigations to better understand subclinical rheumatoid arthritis-associated ILD (RA-ILD); and (5) to achieve her long-term career goal of becoming an independent clinical and translational research investigator in the field of ILD. Mentorship: To achieve these goals, Dr. Lee has assembled a mentoring team comprised of Dr. David Schwartz (primary mentor), an internationally recognized scientist in the field of ILD; Dr. Michael Holers (co- mentor), an internationally recognized expert in the immunologic investigations of early RA; and a research advisory committee that includes Dr. Tasha Fingerlin, an expert statistical geneticist and genetic epidemiologist, and content experts including Dr. Kevin Deane and Dr. Jill Norris. Training and Environment: She has constructed a rigorous career development plan that includes specific coursework, high-impact workshops, and mentorship, centered at CU, which provides the infrastructure, resources and collaborators necessary for high impact clinical research. Research Objective: The overall goal of this research proposal is to define the clinical and molecular/genetic phenotype of subclinical RA-ILD. Relationship to Health: Deaths from RA-ILD are increasing despite an overall decline in RA mortality. Early detection of subclinical RA-ILD will identify patients with a lower burden of lung disease, potentially more salvageable lung, and may reveal novel molecular targets for intervention that are effective in the subclinical and/or early clinical stages of this progressive disease. Rationale: Preliminary data demonstrate clinical, genetic and biologic similarities between RA-ILD and idiopathic pulmonary fibrosis (IPF). This proposal leverages the progress that has been made in the understanding of established and subclinical forms of IPF. Hypothesis: Patients at risk for RA-ILD and IPF have shared clinical, genetic, and biological risk factors. Aims: This research proposal will define the phenotype and estimate the prevalence of subclinical RA-ILD (Aim 1), test the role of the MUC5B variant in subclinical RA-ILD (Aim 2A), and derive and validate a biomarker profile in subclinical RA-ILD (Aim 2B). Approach: To address this hypothesis and accomplish these aims, 400 RA patients will be enrolled and abnormalities of ILD identified using high-resolution computed tomography scans. This information will be used to develop a robust risk prediction algorithm to identify RA patients at highest risk for ILD in the clinical setting. Using this cohort, the genetic and biologic factors associated with subclinical RA-ILD will be investigated.