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: 10543159
• 负责人: Ronny Korstanje
• 金额: $ 44.31万
• 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/10543159
• 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 and Segmental Glomerulosclerosis; Future; Genes; Genetic; Genetic study; Genomic Segment; Glomerulonephritis; Hematuria; Hereditary nephritis; Heterozygote; Histology; Histopathology; Human; Inherited; Kidney; Kidney Diseases; Kidney Failure; Knock-out; Knockout Mice; Lead; Link; Maps; Measures; Molecular; Mus; Mutant Strains Mice; Mutation; Pathogenesis; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Population; Process; Proteins; Public Health; Renal function; Renal glomerular disease; Research; Resolution; Resources; Risk Factors; Sample Size; Sampling; Severities; Severity of illness; Source; Symptoms; Syndrome; Testing; Universities; Urea; Utah; Validation; Variant; X Chromosome; candidate identification; 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.

项目摘要/摘要 Alport综合征是人类遗传性肾小球肾炎，在大多数情况下，导致末期肾脏 疾病。它是导致肾衰竭的最常见遗传性肾小球疾病，是由突变引起的 在编码IV型胶原蛋白的A3，A4或A5链的任何一个基因中 分别）。疾病的发病年龄和严重程度的变化很大，即使在患者之间 类似的突变。在小鼠中的研究表明，肾脏表型高度依赖于遗传 背景。人们普遍认为，修饰符基因有助于这种变异，这可能代表一个来源 新型治疗靶标在Alport综合征和其他肾脏疾病中。我们确定了与人相关的修饰符 与Col4a5突变的一小部分遗传多样的小鼠中的基因（导致X连锁Alport综合征 （XLAS））并验证了这些基因之一FMN1的表达降低导致肾脏不太严重 表型。我们进一步发现，两个候选修饰符基因（PIK3R1和DGKE）调节其他形式 肾脏疾病，包括糖尿病性肾病和造血尿素综合征。在此应用程序中，我们将 通过高分辨率的遗传映射发现XLA的新型候选修饰符基因 遗传上不同的XLA小鼠队列并确认修饰符在 人类。修饰符基因的功能影响和因果关系将在临床前小鼠中评估 XLA和其他形式的肾脏疾病的模型。我们将产生大型，遗传上不同的XLA 与我们以前的人群相结合的小鼠种群将使我们的基因分辨率映射 基因座（AIM 1）。整个外显子组测序和靶向测试，以检测最可能的候选修饰符 将进行人类XLAS谱系中的基因，以确认候选人的翻译相关性 在我们的小鼠研究中发现的修饰基因（AIM 2）。我们将使用可用的淘汰资源和/或CRISPR- Cas9基因编辑在XLAS小鼠模型中测试多达五个候选基因的因果关系（AIM 3A）。我们 将进一步测试这些修饰符基因的因果关系，以肾脏疾病的两种常见形式的小鼠模型： 糖尿病性肾病和局灶性节段性肾小球硬化综合征（AIM 3B）。鉴定基因 负责疾病的发作和严重程度将为理解理解的有意义的见解 肾脏疾病发病机理的基础的分子事件，为发展新颖的基础提供了基础 治疗策略。