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.

项目概要/摘要 IgA 血管炎 (IgAV) 是儿童最常见的系统性血管炎，其特征是 IgA 沉积 存在于皮肤、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病 失败，导致 2% 的病例出现终末期肾病。 IgAV 的确切发病机制目前尚不清楚， IgAV 尚无针对性治疗方法。该提案旨在揭示IgAV的致病机制 使用人类遗传学和系统生物学方法。在目标 1 中，我们将使用 GWAS 方法来发现新颖的 IgAV 的遗传因素，提名候选致病基因，并研究共享遗传 具有其他免疫介导特征的决定因素，以促进药物重新定位。在目标 2 中，我们将研究全球 IgAV 中免疫细胞类型特异性表达和剪接 QTL 的景观，识别 IgAV 特异性基因组 基因调控的调节因子，以及与 GWAS 位点的交叉以阐明 IgAV 的功能后果 风险等位基因并进一步优先考虑候选偶然基因。在目标 3 中，我们将通过以下方式识别驱动基因： 重建疾病特定和细胞类型特定的调控网络，并定义因果遗传 作用于驱动基因上游的改变。这将使我们能够定义基于的发病途径 关于优先驱动基因和基因改变。最后，优先的致病驱动因素和变异 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。综上所述， 拟议的研究将为 IgAV 的遗传决定和发病机制提供新的见解，并将 为检测、治疗和预防 IgAV 的新的和改进的策略的开发做出了重大贡献。我的 总体职业目标是成为一名独立研究者，重点关注确定治疗靶点 通过对群体水平多组学数据进行系统遗传学分析来治疗免疫介导的肾脏疾病。 在这5年的K01职业发展奖期间，我将扩展我在自身免疫和精准方面的培训 医学并获得进行最先进的基于群体的系统遗传学所需的技能 研究。在获奖的最后两年，我将申请R03和R01资助并过渡到独立。 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导师团队 肾病学和复杂性状遗传学专家（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）、分子遗传学和精准医学（Dr. Ionita-Laza） Gharavi，顾问）、人类自身免疫（Winchester 博士，顾问）和职业发展（Rubin 博士， 顾问）。该研究将在哥伦比亚大学进行，这将使我能够获得广泛的研究成果 帮助我成功过渡到独立的资源和培训。