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）是一种儿童孤儿肾病。其机制 皮质类固醇能否诱导某些 NS 患者缓解尚不清楚，其分子基础也不清楚 对皮质类固醇治疗的不同反应。在我们努力了解其分子基础的过程中 类固醇敏感性肾病综合征（SSNS）中的皮质类固醇反应，我们建立了一个 超过 1,000 名 SSNS 和频繁复发/类固醇依赖儿童的生物储存库 （FR/SD）和非 FR/SD 课程。我们在其中的一个子集中进行了全基因组测序 患有家族性疾病的队列，并在 编码clavesin1的基因CLVS1是SSNS的新病因。 Clavesin1 表达为 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，敲低 CLVS1 会增加人足细胞系的凋亡。这 足细胞凋亡增加可以通过皮质类固醇治疗来挽救，类似于类固醇- 在因 H310Y 变异导致 SSNS 的家族中观察到的反应性。拟议的研究将 使用大型 SSNS 患者队列来确定 CLVS1 和其他基因中罕见变异的患病率 足细胞基因以前与 SSNS 相关，并确定其机制 致病性 CLVS1 变异将导致适合皮质类固醇治疗的 NS 表型 治疗。我们的首要假设是 CLVS1 和其他足细胞相关的罕见变异 与非 SSNS 患者相比，与 SSNS 相关的基因在 FR/SD SSNS 患者中更常见 FR/SD SSNS，CLVS1 H310Y 变体通过丢失网格蛋白诱导 SSNS 表型 依赖性内吞作用，可以通过皮质类固醇诱导的网格蛋白增加来挽救 独立的内吞作用。我们将通过以下目标来检验我们的假设：1）使用大 SSNS 患者队列，我们​​之前将识别 CLVS1 和其他足细胞基因的罕见变异 与 SSNS 相关并定义基因型-表型相关性，2) 确定机制 CLVS1 缺陷将导致 NS 和皮质类固醇反应的分子基础。 拟议研究生成的数据将首次深入了解足细胞如何 可以导致 NS 的基因适合用皮质类固醇治疗，并确定新的药物 NS 的目标。

项目成果

Inaxaplin for the treatment of APOL1-associated kidney disease.

• DOI: 10.1038/s41581-023-00721-0
• 发表时间: 2023-08
• 期刊: Nature reviews. Nephrology

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.