Using genomics to elucidate the pathogenesis of granulomatosis with polyangiitis

描述(由申请人提供)：这份K23奖项的申请书为加州大学旧金山分校的风湿病专家Sharon Chung博士提出了补充研究和培训计划。钟博士正在确立自己作为一名翻译研究员的地位，负责开展以患者为导向的系统性脉管炎基因组研究。在这项建议中，钟博士将专注于伴多血管炎的肉芽肿(GPA，以前称为韦格纳肉芽肿)，作为其他系统性脉管炎的潜在模型。该研究计划的总体目标是广泛评估三个主要生物过程--遗传突变、表观遗传失调和异常基因表达--对GPA的疾病易感性和活性的贡献。在拟议的研究中，钟博士将利用尖端的下一代测序技术和最先进的DNA甲基化阵列来识别这些因素。具体地说，钟博士将(1)进行外显子组测序，以确定与GPA疾病易感性相关的影响蛋白质的新基因变异；(2)研究特定白细胞亚群的DNA甲基化(一种表观遗传修饰)如何利用高通量甲基化阵列影响疾病风险和活动；以及(3)确定通过特定白细胞亚群的RNA测序评估的基因表达模式如何随着疾病活动的变化而变化。这些研究，以及结构化的教学和辅导经验，将为钟博士提供以下方面的基本培训：(1)新兴的基因组方法和研究领域，(2)用于分析序列、甲基化和基因表达数据的先进统计技术，以及(3)组织、可视化和处理复杂基因数据集的生物信息学工具。为了方便 凭借这个奖项提供的研究和培训，钟博士组建了一个杰出的多学科指导团队，成员包括Lindsey Criswell博士(进行狼疮和类风湿关节炎遗传流行病学研究的风湿科医生)、郭培仁博士(应用最先进的基因组工具寻找与复杂人类疾病相关的遗传因素的专家)和Joseph Costello博士(脑肿瘤的表观遗传和转录影响的主要研究员)。序列和甲基化数据分析专家约翰·维特博士和马克·西格尔博士将担任生物信息学和统计方法方面的顾问和指导。获得这一K23奖项的培训将使钟博士能够实现她的长期目标，即成为脉管炎基因组学领域的独立研究员和领导者。这些研究的结果将提供关键的初步数据，支持R01应用程序对序列变异、表观遗传修饰和转录变化进行更大、更全面的评估，以更好地了解系统性脉管炎的发病机制。

DESCRIPTION (provided by applicant): This application for a K23 award proposes complementary research and training plans for Dr. Sharon Chung, a rheumatologist at the University of California, San Francisco. Dr. Chung is establishing herself as a translational investigator conducting patient-oriented genomic studies of systemic vasculitis. In this proposal, Dr. Chung will focus on granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis) as a potential model for other systemic vasculitides. The overall goal of the research plan is to broadly assess the contribution of three major biologic processes--genetic mutation, epigenetic dysregulation, and aberrant gene expression--to disease susceptibility and activity in GPA. In the proposed studies, Dr. Chung will utilize cutting-edge next-generation sequencing techniques and state-of-the-art DNA methylation arrays to identify these factors. Specifically, Dr. Chung will (1) perform exome sequencing to identify novel protein-influencing genetic variants associated with GPA disease susceptibility, (2) examine how DNA methylation, an epigenetic modification, of specific leukocyte subsets influences disease risk and activity using high-throughput methylation arrays, and (3) determine how gene expression patterns assessed via RNA-sequencing of specific leukocyte subsets change with disease activity. These studies, as well as structured didactic and tutorial experiences, will provide Dr. Chung essential training in (1) emerging genomic methodologies and fields of research, (2) advanced statistical techniques used to analyze sequence, methylation, and gene expression data, and (3) bioinformatic tools to organize, visualize, and process complex genetic datasets. To facilitate the research and training provided by this award, Dr. Chung has assembled an outstanding multidisciplinary mentoring team comprised of Dr. Lindsey Criswell (a rheumatologist conducting genetic epidemiology studies of lupus and rheumatoid arthritis), Dr. Pui-Yan Kwok (an expert in applying state-of-the-art genomic tools to search for genetic factors associated with complex human diseases), and Dr. Joseph Costello (a leading investigator of epigenetic and transcriptional influences on brain tumors). Drs. John Witte and Mark Segal, experts in analysis of sequence and methylation data, will serve as advisors and provide guidance in bioinformatics and statistical methods. The training obtained with this K23 award will enable Dr. Chung to achieve her long-term objective of becoming an independent investigator and leader in the field of vasculitis genomics. The findings from these studies will provide critical preliminary data supporting an R01 application to conduct larger, more comprehensive evaluations of sequence variation, epigenetic modifications, and transcriptional changes to better understand the pathogenesis of systemic vasculitis.