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Intracellular functions of APOL1 in the kidney

APOL1 在肾脏中的细胞内功能

基本信息

批准号：
10252083
负责人：
Leslie A Bruggeman
金额：
$ 10.47万
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：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2021-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10252083
关键词：
AIDS-Associated Nephropathy Address African American Alleles Animals Apolipoproteins Award Bacterial Artificial Chromosomes Biochemical Biological Models Biological Process CRISPR/Cas technology Cell Line Cells Chronic Kidney Failure Clinical Collection Cultured Cells Data Development Disease Disease Progression Enzymes Event Excision Exposure to Focal Segmental Glomerulosclerosis Functional disorder Genes Genetic Risk Genotype Guide RNA HIV Infections Human Hypertension Immune signaling Inherited Innate Immune Response Kidney Kidney Diseases Knock-out Link Methods Pathogenesis Pattern Pattern recognition receptor Physiological Plasmids Pluripotent Stem Cells Poly I-C Protocols documentation Recombinant DNA Risk Role System Time Transgenic Mice United States Variant Work base disease stressor environmental stressor gain of function genetic variant glomerulosclerosis insight loss of function mouse model nano-string new therapeutic target novel phenotypic biomarker podocyte protein function racial health disparity response risk variant therapy design trait

项目摘要

ABSTRACT Chronic kidney disease (CKD) in African Americans is one of the largest racial health disparities in the United States. The cause for the increased risk has been attributed to recessive inheritance of allelic variants in the gene for apolipoprotein L1 (APOL1). These APOL1 variants, known as G1 and G2, do not cause CKD on their own, but CKD is caused by a combination of the inherited genetic risk plus exposure to a triggering environmental stressor. The biological function of APOL1 in the kidney and the mechanism of pathogenesis in the setting of a disease stressor remain unclear. Our recent studies have demonstrated, for the first time, a function for the common APOL1 allele, known as G0, in providing protection against podocyte losses and glomerulosclerosis in one of the CKDs highly associated with carriage of APOL1 risk alleles (HIV-associated nephropathy). The fundamental cause of this protection appears to be linked to a role of APOL1 G0 in supporting innate immune signaling events through pattern recognition receptors. In addition, since APOL1 risk is a recessively inherited trait, this also suggests CKD may be cause, in part, by a loss of this beneficial function. To advance these studies, we propose to develop additional cell-based and animal-based model systems to investigate the function of APOL1 G0 in innate immune responses, and how these responses are altered in the presence of the risk variants G1 and G2. These new cell and animal based systems will allow for both biochemical studies to address mechanism of action and physiological studies to assess impact on CKD progression, and should provide insight into gain- versus loss-of-function mechanisms associated with the recessive inheritance of APOL1 risk alleles. Determining the contribution of G0 function versus risk variant dysfunction will have important clinical impact on further therapy design, as it will establish whether replacement of G0 or suppression of the risk variants would be the more effective strategy.

抽象的非裔美国人的慢性肾病（CKD）是美国最大的种族健康差异之一。风险增加的原因归因于载脂蛋白 L1 (APOL1) 基因等位基因变异的隐性遗传。这些 APOL1 变异体（称为 G1 和 G2）本身不会引起 CKD，但 CKD 是由遗传性遗传风险加上暴露于触发性环境压力源共同引起的。 APOL1 在肾脏中的生物学功能以及疾病应激源背景下的发病机制仍不清楚。我们最近的研究首次证明了常见的 APOL1 等位基因（称为 G0）的功能，可以在与携带 APOL1 风险等位基因（HIV 相关肾病）高度相关的 CKD 中提供针对足细胞损失和肾小球硬化的保护。这种保护的根本原因似乎与 APOL1 G0 通过模式识别受体支持先天免疫信号事件的作用有关。此外，由于 APOL1 风险是一种隐性遗传特征，这也表明 CKD 可能部分是由这种有益功能的丧失引起的。为了推进这些研究，我们建议开发额外的基于细胞和动物的模型系统，以研究 APOL1 G0 在先天免疫反应中的功能，以及这些反应在存在风险变异 G1 和 G2 的情况下如何改变。这些新的基于细胞和动物的系统将允许进行生化研究以解决作用机制，以及进行生理学研究以评估对 CKD 进展的影响，并应提供对与 APOL1 风险等位基因隐性遗传相关的功能获得与功能丧失机制的深入了解。确定 G0 功能与风险变异功能障碍的贡献将对进一步的治疗设计产生重要的临床影响，因为它将确定替代 G0 或抑制风险变异是否是更有效的策略。