Uncovering novel mechanisms and potential therapeutic targets for IgA vasculitis through GWAS and systems-level analysis of regulatory networks.

通过 GWAS 和调节网络的系统级分析揭示 IgA 血管炎的新机制和潜在治疗靶点。

• 批准号: 10723651
• 负责人: Lili Liu
• 金额: $ 15.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-24 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723651
• 关键词: 19q13; 1q21; 2q37.1; Address; Adult; Affect; Asian ancestry; Autoimmune Diseases; Autoimmunity; Award; Blood; Blood Vessels; Cells; Child; Childhood; Chromosome Mapping; Clinical; Clinical Data; Communicable Diseases; Complex Genetic Trait; Data; Data Set; Deposition; Detection; Development; Disease; East Asian; End stage renal failure; Ethnic Origin; European; Foundations; Funding; Gastrointestinal tract structure; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Determinism; Genetic Medicine; Genetic Predisposition to Disease; Genetic study; Genomics; Goals; HLA-DRB1; Health; Hematuria; Henoch-Schoenlein Purpura; Human; Human Genetics; IgA receptor; Immune; Immune Targeting; Immunoglobulin A; Immunologics; Individual; Inflammatory; Interleukin 6 Receptor; Joints; K-Series Research Career Programs; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Maps; Mediating; Mentors; Mentorship; Meta-Analysis; Modeling; Molecular Medicine; Multiomic Data; Nephrology; Organ; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Population Analysis; Positioning Attribute; Prevention; Prevention strategy; Proteinuria; Proteome; Quantitative Trait Loci; RNA Splicing; Regulator Genes; Research; Research Personnel; Research Training; Resources; Risk; Signal Transduction; Skin; Spliced Genes; Susceptibility Gene; System; Systems Biology; Testing; Training; Translations; Universities; Variant; Vasculitis; Work; career; career development; case control; causal variant; cell type; cohort; drug development; functional genomics; gene function; gene regulatory network; genetic analysis; genetic architecture; genetic variant; genome wide association study; genome-wide; improved; insight; multidisciplinary; new therapeutic target; novel; peripheral blood; population based; precision medicine; prevent; reconstruction; risk variant; skill acquisition; therapeutic target; tocilizumab; trait; transcriptome; transcriptomics; treatment strategy

PROJECT SUMMARY/ABSTRACT IgA vasculitis (IgAV) is the most common form of systemic vasculitis in children, characterized by IgA deposition in the small blood vessels of skin, kidney, gastrointestinal tract, and joints. Among patients with IgAV, 20%-55% have renal involvement. Renal manifestations include hematuria, proteinuria, and variable degree of kidney failure, leading to end stage renal disease in 2% cases. The exact pathogenesis of IgAV is currently unknown, and there are no targeted treatments for IgAV. This proposal aims at uncovering pathogenic mechanism of IgAV using human genetics and systems biology approaches. In Aim 1, we will use GWAS approach to discover novel genetic factors for IgAV, nominate candidate disease-causing genes, and investigate shared genetic determinants with other immune-mediated traits to facilitate drug repositioning. In Aim 2, we will study the global landscape of immune cell type-specific expression and splicing QTLs in IgAV, identify IgAV-specific genomic regulators for gene regulation, and intersection with GWAS loci to elucidate the functional consequences of IgAV risk alleles and further prioritize candidate casual genes. In Aim 3, we will identify the driver genes through reconstruction of disease context-specific and cell-type specific regulatory networks, and define causal genetic alternations acting upstream of the driver genes. This will allow us to define the pathogenetic pathways based on the prioritized driver genes and genetic alternations. Lastly, the prioritized pathogenetic drivers and variants will be tested against clinical data to facilitate translation of these findings into clinical benefits. In summary, the proposed research will provide new insights into the genetic determination and pathogenesis of IgAV,and will significantly contribute to the development of new and improved strategies to detect, treat, and prevent IgAV. My overarching career goal is to become an independent investigator with a focus on identifying therapeutic targets for immune-mediated kidney diseases through systems genetics analyses of population-level multi-omics data. During this 5-year K01 Career Development Award, I will expand my training in autoimmunity and precision medicine and to acquire the skills necessary to conduct state-of-the-art population-based systems genetics studies. In the last two years of the award, I will apply for R03 and R01 funding and transition to independence. To guide and support my research and training goals, I have assembled a multidisciplinary mentorship team of experts in Nephrology and Complex Traits Genetics (Dr. Kiryluk, primary mentor), Systems Biology (Dr. Califano, co-mentor), Statistical Genetics (Dr. Ionita-Laza, co-mentor), Molecular Genetics and Precision Medicine (Dr. Gharavi, Advisor), Human Autoimmunity (Dr. Winchester, Advisor), and Career Development (Dr. Rubin, Advisor). The research will be conducted at Columbia University, which will give me access to extensive research resources and training to help me successfully transition to independence.

项目摘要/摘要 IgA血管炎是儿童最常见的系统性脉管炎，以IgA沉积为特征。 在皮肤、肾脏、胃肠道和关节的小血管中。在IgAV患者中，20%-55% 有肾脏受累。肾脏表现包括血尿、蛋白尿和不同程度的肾脏。 失败，导致终末期肾病的病例占2%。目前，IgAV的确切发病机制尚不清楚。 而且目前还没有针对IgAV的靶向治疗方法。这项建议旨在揭示IgAV的致病机制 利用人类遗传学和系统生物学的方法。在目标1中，我们将使用GWAS方法来发现小说 免疫球蛋白病毒的遗传因素，提名候选致病基因，并调查共享基因 具有其他免疫介导性的决定因素，以促进药物重新定位。在目标2中，我们将研究全球 免疫细胞类型特异性表达和剪接QTL在IgAV中的图谱，鉴定IgAV特异性基因组 基因调控的调节者，以及与Gwas基因座的交集以阐明IgAV的功能后果 风险等位基因，并进一步确定候选偶然基因的优先顺序。在目标3中，我们将通过以下方式识别驱动基因 重建特定于疾病背景和特定于细胞类型的调控网络，并确定因果遗传 在驾驶员基因的上游起作用的变化。这将使我们能够定义基于 关于优先驱动基因和基因变化。最后，按优先顺序排列的致病动因和变异 将根据临床数据进行测试，以促进将这些发现转化为临床益处。总而言之， 拟议的研究将为IgAV的基因决定和发病机制提供新的见解，并将 极大地促进了新的和改进的战略的发展，以检测、治疗和预防IgAV。我的 首要的职业目标是成为一名独立的研究人员，专注于确定治疗目标 通过对人群水平的多组学数据进行系统遗传学分析，对免疫介导的肾脏疾病进行研究。 在这个为期5年的K01职业发展奖期间，我将扩大我在自身免疫和精确度方面的训练 医学和获得进行最先进的基于种群的系统遗传学所需的技能 学习。在获奖的最后两年，我将申请R03和R01资金，并过渡到独立。 为了指导和支持我的研究和培训目标，我组建了一个多学科指导团队， 肾病和复杂性状遗传学(Kiryluk博士，主要导师)、系统生物学(Califano博士， 共同导师)、统计遗传学(Ionita-Laza博士，共同导师)、分子遗传学和精密医学(Dr。 Gharavi，顾问)、人类自身免疫(Winchester博士，顾问)和职业发展(Rubin博士， 顾问)。这项研究将在哥伦比亚大学进行，这将使我有机会进行广泛的研究 帮助我成功过渡到独立的资源和培训。