Human iPSC-derived Podocytes to Study APOL1 High-Risk Variants

人 iPSC 衍生的足细胞用于研究 APOL1 高风险变异体

基本信息

批准号：
10607362
负责人：
Lauren Elizabeth Haines
金额：
$ 3.68万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607362
关键词：
Adult Affect African African American population African Trypanosomiasis Alleles Amino Acids Animal Model Apolipoproteins Belief Biology C-terminal Cell Line Cell model Cells Cessation of life Chronic Kidney Failure Consumption Coupled Cytoplasm Cytoskeleton Data Development Dialysis procedure Disease Disease Progression End stage renal failure Epithelium European Exhibits Experimental Designs Exposure to Filtration Foot Process Functional disorder Genes Genetic Engineering Genotype Glomerular Capillary Goals HIV Heterozygote Human Hypertension Impairment Incidence Individual Injury Injury to Kidney Kidney Kidney Diseases Kidney Transplantation Knowledge Link Liquid substance Maintenance Mediating Modeling Pathogenicity Pathology Patients Physiological Point Mutation Population Primates Process Proteins Protocols documentation Quality of life Renal function Renal glomerular disease Research Resort Risk Series Signal Pathway Structure Therapeutic Intervention Time United States Urine Variant Virus Diseases Work biological adaptation to stress cell type curative treatments cytotoxic cytotoxicity directed differentiation health disparity high risk in vivo induced pluripotent stem cell injured kidney allograft migration non-diabetic novel overexpression podocyte resistance allele response risk variant slit diaphragm stressor transcriptome sequencing wasting

项目摘要

PROJECT SUMMARY/ABSTRACT. . Kidney disease status is characterized by how efficiently the kidney is able to remove excess fluids and waste. Podocytes within the glomerulus are integral to forming the barrier needed for this filtration. An estimated 15% of adults in the US have chronic kidney disease (CKD), but there are no curative treatment options for CKD and patients must resort to time-consuming dialysis or undergoing a kidney transplant to maintain a quality of life during disease progression. The African American population of sub-Saharan descent has a 3.5-fold increased risk for end-stage kidney disease compared to populations of European descent. This incidence discrepancy is, in part, due to two pathogenic variants G1 and G2 in the apolipoprotein L1 (APOL1) gene. Individuals with the presence of one high-risk allele are resistant to African sleeping sickness, but the presence of two high-risk alleles significantly predisposes to kidney disease. As APOL1 is only found in humans and some primates, this work utilizes isogenic human iPSC lines genetically engineered to contain APOL1 variant genotypes. The mechanism of APOL1-mediated kidney diseases is not known but correlates with podocyte population depletion. This depletion is thought to be linked to foot process effacement, a podocyte stress response dictated by cytoskeletal rearrangements that cause the processes to simplify and flatten to flatten, leading to decreased kidney function. This study proposes high-risk APOL1 podocytes are intrinsically different compared to reference APOL1 podocytes. Variant APOL1 iPSC lines will be directly differentiated into pure podocyte populations and will be used to determine if the presence of high-risk APOL1 interferes with podocyte cytoskeleton dynamics. Further, this work will utilize a Design of Experiment (DoE) approach to detect the effects of synergistic inputs involved in podocyte biology to determine if high-risk APOL1 podocytes are intrinsically different. This research will assess human-specific aspects of podocyte biology in a representative and homogenous cell population, providing an opportunity to gain an understanding of the mechanism of APOL1-mediated diseases. Data generated will provide directly translatable and desperately needed therapeutic intervention to kidney disease injury and progression.

项目摘要/摘要。。肾脏疾病状况的特征是肾脏能够消除多余的液体和废物的效率。肾小球内的足细胞是形成该过滤所需的屏障不可或缺的。估计15％美国的成年人患有慢性肾脏疾病（CKD），但CKD没有治疗方法患者必须诉诸时必的透析或接受肾脏移植以保持质量疾病进展过程中的生活。撒哈拉以南血统的非裔美国人人口有3.5倍与欧洲血统的人群相比，终末期肾脏疾病的风险增加。这个发病率差异部分是由于载脂蛋白L1（APOL1）基因中的两个致病变异G1和G2。具有一个高风险等位基因的人对非洲熟睡的疾病有抵抗力，但存在两个高风险等位基因在肾脏疾病中显着易患。因为Apol1仅在人类中发现一些灵长类基因型。 APOL1介导的肾脏疾病的机制尚不清楚，但与足细胞相关人口枯竭。这种耗竭被认为与脚步效率有关，是足细胞应力响应由细胞骨架重排决定，导致过程简化并变平，导致肾功能下降。这项研究提出高风险的Apol1足细胞本质上不同与参考apol1足细胞相比。变体APOL1 IPSC线将直接分化为纯足细胞种群，将用于确定是否存在高风险Apol1的存在细胞骨架动力学。此外，这项工作将利用实验设计（DOE）的设计来检测涉及足细胞生物学的协同输入的影响，以确定高风险的Apol1足细胞是否是本质上不同。这项研究将评估代表性的足细胞生物学的人类特定方面和同质细胞种群，提供了一个机会，以了解 APOL1介导的疾病。生成的数据将直接翻译和迫切需要治疗干预肾脏疾病损伤和进展。