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.

项目总结/摘要 Alport综合征是一种人类遗传性肾小球肾炎，其在大多数情况下导致终末期肾损害。 疾病它是最常见的遗传性肾小球疾病导致肾功能衰竭，是由突变引起的 在编码IV型胶原α 3、α 4或α 5链（COL 4A 3、COL 4A 4和COL 4A 5）的基因中的任一种中， 分别）。在发病年龄和疾病严重程度方面存在很大差异，即使在患有 类似的突变。小鼠研究表明，肾脏表型高度依赖于遗传因素， 背景人们普遍认为，修饰基因有助于这种变化，这可能是一个来源， Alport综合征和其他肾脏疾病的新治疗靶点。我们发现了人类相关的修饰物 在一小群具有Col 4a 5突变（导致X连锁Alport综合征）的遗传多样性小鼠中， （XLAS）），并验证了这些基因之一，Fmn 1的表达减少，导致不太严重的肾功能损害。 表型我们进一步发现，两个候选修饰基因（Pik 3r 1和Dgke）调节其他形式的 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 通过大规模的高分辨率遗传作图发现XLAS的新候选修饰基因， 遗传多样性XLAS小鼠队列，并证实了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的模型。我们将生产一个巨大的，基因多样的XLAS 小鼠群体，结合我们以前的人口，将允许我们基因分辨率映射的修改器， 基因座（Aim 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物 将进行人类XLAS谱系中的基因，以确认候选基因的翻译相关性。 在我们的小鼠研究中发现的修饰基因（Aim 2）。我们将使用可用的基因敲除资源和/或CRISPR- Cas9基因编辑，以测试XLAS小鼠模型中多达五个候选基因的因果关系（Aim 3A）。我们 将在两种常见肾脏疾病的小鼠模型中进一步测试这些修饰基因的因果关系： 糖尿病肾病和局灶节段性肾小球硬化综合征（Aim 3B）。基因鉴定 负责疾病的发病和严重程度将提供有意义的见解，了解 肾脏疾病发病机制的分子事件，并为开发新的 治疗策略