GENETIC BASIS OF CORTICOSTEROID RESPONSE IN CHILDHOOD NEPHROTIC SYNDROME

儿童肾病综合征皮质类固醇反应的遗传基础

• 批准号: 10382270
• 负责人: Rasheed Adebayo Gbadegesin
• 金额: $ 20.13万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-02 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382270
• 关键词: Adrenal Cortex Hormones; Affect; Antioxidants; Apoptosis; Automobile Driving; Binding; Biological Markers; CRISPR/Cas technology; Cell Line; Child; Childhood; Clathrin; Clinical; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Defect; Dexamethasone; Disease; Disease remission; Edema; Endocytosis; Exposure to; Failure; Familial disease; Family; Foundations; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Genotype; Glucocorticoids; Growth; Homeostasis; Human; Kidney Diseases; Knock-in; Knock-out; Maintenance; Mediating; Molecular; Morphology; Nephrotic Syndrome; Orphan; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Prevalence; Proteins; Reactive Oxygen Species; Relapse; Siblings; Signal Pathway; Steroids; Testing; Therapeutic; Time; Transcription Alteration; Variant; Zebrafish; alpha Tocopherol; biobank; cohort; combat; genome sequencing; glomerular filtration; individualized medicine; infection risk; insight; knock-down; late endosome; loss of function; nephrin; new therapeutic target; next generation; novel; novel therapeutics; patient population; phosphatidylinositol 3,5-diphosphate; podocyte; rare variant; response; side effect; small hairpin RNA; targeted sequencing; transcriptome sequencing; translational study; treatment response; whole genome

Nephrotic syndrome (NS) is an orphan kidney disease in children. The mechanisms by which corticosteroids induce remission in some patients with NS is not known, nor is the molecular basis of variable response to corticosteroid therapy. In our efforts to understand the molecular basis of corticosteroid response in steroid sensitive nephrotic syndrome (SSNS), we have established a biorepository of more than 1,000 children with SSNS and frequent relapsing/steroid dependent (FR/SD) and non-FR/SD course. We carried out whole genome sequencing in a subset of this cohort with familial disease and identified a segregating rare pathogenic variant H310Y in the gene CLVS1 encoding for clavesin1 as a new cause of SSNS. Clavesin1 is expressed in podocytes and is required for the normal morphology of late endosomes. In preliminary data, we have shown that knockdown of CLVS1 increases apoptosis in human podocyte cell lines. The increased podocyte apoptosis can be rescued by corticosteroid treatment, mimicking the steroid- responsiveness observed in the family with SSNS due to H310Y variant. The proposed study will use a large SSNS patient cohort to determine the prevalence of rare variants in CLVS1 and other podocyte genes previously associated with SSNS, and determine the mechanisms by which pathogenic CLVS1 variants will cause NS phenotypes that are amenable to corticosteroid treatment. Our overarching hypothesis is that rare variants in CLVS1 and other podocyte related genes associated with SSNS are more common in patients with FR/SD SSNS compared to non- FR/SD SSNS, and that the CLVS1 H310Y variant induces an SSNS phenotype by loss of clathrin dependent endocytosis that can be rescued by a corticosteroid-induced increase in clathrin independent endocytosis. We will test our hypothesis through the following aims: 1) Using a large SSNS patient cohort, we will identify rare variants in CLVS1 and other podocyte genes previously associated with SSNS and define genotype-phenotype correlation, 2) Determine the mechanisms by which defects in CLVS1 will cause NS and the molecular basis for corticosteroid response. Data generated from the proposed study will for the first time, provide insight into how podocyte genes can cause NS that is amenable to therapy with corticosteroids and identify new druggable targets for NS.

肾病综合征(NS)是儿童的一种孤儿肾脏疾病。它们的作用机制 皮质类固醇对一些NS患者的缓解作用尚不清楚，其分子基础也不清楚。 对皮质类固醇治疗有不同的反应。在我们努力理解的分子基础上 激素敏感型肾病综合征(SSNS)的糖皮质激素反应 1,000多名患有SSNS并经常复发/类固醇依赖的儿童的生物信息库 (FR/SD)和非FR/SD课程。我们对其中的一部分进行了全基因组测序 在家族性疾病的队列中发现了一个分离的罕见致病变异体H310Y Clavesin1基因是SSNS的新致病基因。Clavesin1的表达形式为 足细胞，是晚期内体正常形态所必需的。在初步数据中，我们 研究表明，CLVS1基因敲除可增加人足细胞系的细胞凋亡率。这个 足细胞凋亡率的增加可以通过皮质类固醇治疗来挽救，类似类固醇- 在患有SSNS的家庭中观察到H310Y变异所致的反应性。拟议的研究将 使用大量SSNS患者队列来确定CLVS1和其他 足细胞基因以前与SSN相关，并确定通过什么机制 致病性CLVS1变异将导致对皮质类固醇敏感的NS表型 治疗。我们的主要假设是CLVS1和其他足细胞中的罕见变异与 与非FR/SD SSNS患者相比，与SSN相关的基因更常见 FR/SD SSNS，CLVS1 H310Y变异体通过丢失网状蛋白诱导SSNS表型 依赖的内吞作用可通过皮质类固醇诱导的网状蛋白增加来挽救 独立的内吞作用。我们将通过以下目标来验证我们的假设：1)使用大型 SSNS患者队列，我们将鉴定CLVS1和其他足细胞基因的罕见变异 与SSNS相关并定义基因-表型相关性，2)确定机制 其中CLVS1的缺陷将导致NS和皮质激素反应的分子基础。 这项拟议研究产生的数据将首次提供足细胞如何 基因可以导致对皮质类固醇激素治疗顺从的NS，并发现新的可治疗药物 NS的目标。

项目成果

Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis.

• DOI: 10.1172/jci.insight.152102
• 发表时间: 2022-01-25
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Lane, Brandon M.;Chryst-Stangl, Megan;Wu, Guanghong;Shalaby, Mohamed;El Desoky, Sherif;Middleton, Claire C.;Huggins, Kinsie;Sood, Amika;Ochoa, Alejandro;Malone, Andrew F.;Vancini, Ricardo;Miller, Sara E.;Hall, Gentzon;Kim, So Young;Howell, David N.;Kari, Jameela A.;Gbadegesin, Rasheed
• 通讯作者: Gbadegesin, Rasheed

The case for treatment of monogenic SRNS with calcineurin inhibitors.

• DOI: 10.1016/j.kint.2023.02.017
• 发表时间: 2023-05
• 期刊: KIDNEY INTERNATIONAL
• 影响因子: 19.6
• 作者: Lane, Brandon M.;Gbadegesin, Rasheed A.
• 通讯作者: Gbadegesin, Rasheed A.