RIGERR: Resources for Investigating Genetic and Epigenetic Regulation of Renal Disease

RIGERR：研究肾脏疾病遗传和表观遗传调控的资源

• 批准号: 10879669
• 负责人: MINGYU LIANG
• 金额: $ 98.49万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-03 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10879669
• 关键词: RIGERR; Resources; Investigating; Genetic; Epigenetic

SUMMARY Identifying functional sequence variants and effector genes for disease-associated functional variants, understanding how the variants influence effector genes and disease, and utilizing this information to advance precision medicine are among the most important yet formidable challenges in current genetic research of common diseases. Sequence variants identified by genome-wide association studies (GWAS) can have substantial effects on gene expression, and identification of GWAS effector genes and the mechanisms involved has important clinical and scientific implications. Chronic kidney disease occurs in more than 10% of the general population. GWAS in up to 1 million people have identified more than 200 genomic loci associated with renal function, chronic kidney disease, or urinary albumin-to-creatinine ratio. Haplotypes in linkage disequilibrium (LD) at these loci contain more than 7,000 unique single nucleotide polymorphisms (SNPs). Very few studies have gone beyond associations to ascertain the effect of kidney-associated SNPs on gene expression or investigate the mechanisms involved. Such studies would have to overcome substantial challenges including the tissue-specific nature of the effect of regulatory SNPs on gene expression. Many LD regions are thousands of base pairs long and may contain dozens of SNPs. These long LD regions are particularly difficult to study. We have developed a unique approach and innovative methods for definitively and mechanistically linking haplotype variants, including long haplotypes, to genes in specific disease-relevant cell types. In RIGERR (Resources for Investigating Genetic and Epigenetic Regulation of Renal Disease), we propose to use this suite of sophisticated technologies to generate a large collection of innovative tools and resources to transform genetic and epigenetic research of kidney disease broadly. Aim 1 of RIGERR is to generate more than 100 lines of human induced pluripotent stem cells genetically engineered to contain readily editable or precisely reconstituted haplotypes or high-penetrance variants associated with kidney function or disease. These edited cell lines will be provided to the research community for a wide range of molecular, functional, or drug testing studies for kidney disease. In Aim 2, we will produce novel datasets and establish a workflow for utilizing these unprecedented resources to conduct mechanistic and in vivo studies of kidney function and disease, using albuminuria as an example. We have obtained exciting preliminary data that strongly support the conceptual and technical feasibility of RIGERR.

概括 鉴定与疾病相关的功能变异的功能序列变异和效应基因，了解变体如何影响效应基因和疾病，并利用这些信息来推进精度医学，这是当前对常见疾病的遗传研究中最重要但艰巨的挑战之一。通过全基因组关联研究（GWAS）鉴定的序列变体可以对基因表达产生实质性影响，并且鉴定GWAS效应基因和所涉及的机制具有重要的临床和科学意义。慢性肾脏疾病发生在超过10％的普通人群中。多达100万人的GWAS已确定了200多个与肾功能，慢性肾脏疾病或尿白蛋白与促甲状腺素比率相关的基因组基因座。连锁不平衡（LD）中的单倍型包含7,000多个独特的单核苷酸多态性（SNP）。很少有研究超越关联，以确定与肾脏相关的SNP对基因表达的影响或研究所涉及的机制。这样的研究将必须克服重大挑战，包括调节性SNP对基因表达的影响的组织特异性。许多LD区域长成千上万的碱基对，可能包含数十个SNP。这些长LD区域特别困难。 我们开发了一种独特的方法和创新方法，用于将单倍型变体（包括长单倍型）与特定疾病相关的细胞类型中的基因联系起来。在Rigerr（用于调查肾脏疾病的遗传和表观遗传调节的资源）中，我们建议使用这套精致技术来生成大量创新工具和资源，以转化肾脏疾病的遗传和表观遗传学研究。 Rigerr的目标1是生成100行人类诱导的多能干细胞基因设计的，以包含可易于编辑或精确重构的单倍型或与肾功能或疾病相关的高渗透变体。这些编辑的细胞系将提供给研究界，以进行肾脏疾病的各种分子，功能或药物测试研究。在AIM 2中，我们将生产新的数据集并建立一个工作流程，以利用这些前所未有的资源来进行肾功能和疾病的机械和体内研究，以蛋白尿症为例。我们获得了令人兴奋的初步数据，这些数据强烈支持Rigerr的概念和技术可行性。