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

项目总结/摘要 伊加血管炎（IgAV）是儿童最常见的系统性血管炎，以伊加沉积为特征 在皮肤、肾脏、胃肠道和关节的小血管中。在IgAV患者中，20%-55% 肾脏受累。肾脏表现包括血尿、蛋白尿和不同程度的肾 衰竭，导致终末期肾病的2%的情况下。IgAV的确切发病机制目前尚不清楚， 并且没有针对IgAV的靶向治疗。本研究旨在揭示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方法来发现新的 IgAV的遗传因素，提名候选致病基因，并调查共同的遗传因素， 决定因素与其他免疫介导的性状，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，鉴定IgAV特异性基因组 调节基因调控，并与GWAS基因座交叉，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因果基因。在目标3中，我们将通过以下方式识别驱动基因： 重建疾病背景特异性和细胞类型特异性调控网络，并定义因果遗传学 驱动基因上游的交替。这将使我们能够确定致病途径的基础上， 优先的驱动基因和基因变异。最后，优先的致病驱动因素和变体 将根据临床数据进行测试，以促进将这些发现转化为临床获益。总之， 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 这将大大有助于开发新的和改进的策略来检测，治疗和预防IgAV。我 总体职业目标是成为一名独立的研究者，专注于确定治疗目标 通过对人群水平多组学数据的系统遗传学分析， 在这个为期5年的K 01职业发展奖期间，我将扩大我在自身免疫和精确度方面的培训 医学和获得必要的技能，进行最先进的人口为基础的系统遗传学 问题研究在获奖的最后两年，我将申请R 03和R 01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的导师团队， 肾脏学和复杂性状遗传学专家（Kiryluk博士，主要导师），系统生物学专家（Califano博士， 共同导师），统计遗传学（博士Ionita-Laza，共同导师），分子遗传学和精密医学（博士 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，这将使我获得广泛的研究 资源和培训，帮助我成功地过渡到独立。

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.