Identification of Kidney Disease Modifier Genes in Mouse and Human Alport Syndrome

小鼠和人类 Alport 综合征中肾脏疾病修饰基因的鉴定

• 批准号: 10341489
• 负责人: Ronny Korstanje
• 金额: $ 45.78万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10341489
• 关键词: Affect; Age of Onset; Aging; Albuminuria; Biological; COL4A3 gene; CRISPR/Cas technology; Candidate Disease Gene; Chromosome Mapping; Clinical; Collagen Type IV; Data; Detection; Diabetic Nephropathy; Disease Progression; Drug Design; Economics; End stage renal failure; Etiology; Event; Factor X; Family; Female; Focal Segmental Glomerulosclerosis; Future; Genes; Genetic; Genetic study; Genomic Segment; Glomerulonephritis; Hematuria; Hereditary nephritis; Histology; Histopathology; Human; Inherited; Kidney; Kidney Diseases; Kidney Failure; Knock-out; Knockout Mice; Lead; Link; Measures; Molecular; Mus; Mutant Strains Mice; Mutation; Pathogenesis; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Play; Population; Process; Proteins; Public Health; Renal function; Renal glomerular disease; Research; Resolution; Resources; Risk Factors; Role; Sample Size; Sampling; Severities; Severity of illness; Source; Suggestion; Symptoms; Syndrome; Testing; Universities; Urea; Utah; Validation; Variant; X Chromosome; candidate identification; chromosome mutation; cohort; combat; detection test; diabetic; exome sequencing; genetic analysis; genetic pedigree; genome-wide; glomerular basement membrane; human disease; improved; insight; kindred; male; member; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; protective factors; translational impact

PROJECT SUMMARY/ABSTRACT Alport syndrome is a human hereditary glomerulonephritis, which in most cases, results in end-stage renal disease. It is the most common inherited glomerular disease leading to renal failure and is caused by mutations in any one of the genes encoding a3, a4, or a5 chains of type IV collagen (COL4A3, COL4A4, and COL4A5, respectively). There is large variation in the age of onset and severity of the disease, even between patients with similar mutations. Studies in mice have shown that the renal phenotype is highly dependent on the genetic background. It is widely accepted that modifier genes contribute to this variation, which could represent a source of novel therapeutic targets in Alport syndrome and other renal diseases. We identified human-relevant modifier genes in a small cohort of genetically diverse mice with a Col4a5 mutation (leading to X-linked Alport syndrome (XLAS)) and validated that decreased expression of one of these genes, Fmn1, leads to a less severe renal phenotype. We further found that two of the candidate modifier genes (Pik3r1 and Dgke) modulate other forms of kidney disease, including diabetic nephropathy and hematolytic urea syndrome. In this application we will discover novel candidate modifier genes of XLAS by high-resolution genetic mapping in a large genetically diverse XLAS mouse cohort and confirm the translational relevance of the modifiers in humans. The functional impact and causality of the modifier genes will be assessed in preclinical mouse models of XLAS and other forms of kidney disease. We will generate a large, genetically diverse XLAS mouse population that, combined with our previous population, will allow us gene-resolution mapping of modifier loci (Aim 1). Whole exome sequencing and targeted testing for the detection of the most likely candidate modifier genes in human XLAS pedigrees will be conducted to confirm the translational relevance of the candidate modifier genes found in our mouse studies (Aim 2). We will use available knockout resources and/or CRISPR- Cas9 gene editing to test causality of as many as five candidate genes in the XLAS mouse model (Aim 3A). We will further test these modifier genes for causality in mouse models of two common forms of kidney disease: diabetic nephropathy and focal segmental glomerulosclerosis syndrome (Aim 3B). Identification of the genes responsible for the onset and severity of disease will provide meaningful insights into understanding the molecular events underlying the pathogenesis of kidney disease and provide the basis for developing novel therapeutic strategies.

项目概要/摘要 奥尔波特综合征是一种人类遗传性肾小球肾炎，在大多数情况下会导致终末期肾病 疾病。它是导致肾衰竭的最常见遗传性肾小球疾病，由突变引起 在编码 IV 型胶原的 a3、a4 或 a5 链（COL4A3、COL4A4 和 COL4A5）的任何一种基因中， 分别）。即使在患有以下疾病的患者之间，发病年龄和疾病严重程度也存在很大差异 类似的突变。对小鼠的研究表明，肾脏表型高度依赖于遗传 背景。人们普遍认为修饰基因会导致这种变异，这可能是一种来源 阿尔波特综合征和其他肾脏疾病的新治疗靶点。我们确定了与人类相关的修饰符 一小群具有 Col4a5 突变（导致 X 连锁 Alport 综合征）的基因多样化小鼠的基因 (XLAS)) 并验证了这些基因之一 Fmn1 表达的减少会导致肾功能不那么严重 表型。我们进一步发现两个候选修饰基因（Pik3r1 和 Dgke）调节其他形式 肾脏疾病，包括糖尿病肾病和溶血性尿素综合征。在这个应用程序中我们将 通过大样本的高分辨率遗传图谱发现 XLAS 的新候选修饰基因 遗传多样性的 XLAS 小鼠群体并确认修饰物的翻译相关性 人类。将在临床前小鼠中评估修饰基因的功能影响和因果关系 XLAS 和其他形式的肾脏疾病模型。我们将产生一个大型的、基因多样化的 XLAS 小鼠群体，与我们之前的群体相结合，将允许我们对修饰符进行基因分辨率映射 位点（目标 1）。全外显子组测序和靶向测试，用于检测最可能的候选修饰因子 将检测人类 XLAS 谱系中的基因，以确认候选者的翻译相关性 我们在小鼠研究中发现的修饰基因（目标 2）。我们将使用可用的基因敲除资源和/或 CRISPR- Cas9 基因编辑可测试 XLAS 小鼠模型中多达 5 个候选基因的因果关系 (Aim 3A)。我们 将进一步测试这些修饰基因在两种常见肾脏疾病的小鼠模型中的因果关系： 糖尿病肾病和局灶节段性肾小球硬化综合征（目标 3B）。基因鉴定 负责疾病的发作和严重程度将为理解疾病提供有意义的见解 肾脏疾病发病机制的分子事件，并为开发新的药物提供基础 治疗策略。