Intracellular functions of APOL1 in the kidney

APOL1 在肾脏中的细胞内功能

• 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
• 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

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.

摘要 非裔美国人的慢性肾脏病（CKD）是美国最大的种族健康差异之一。风险增加的原因被归因于载脂蛋白L1（APOL 1）基因中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是由遗传遗传风险加上暴露于触发环境压力因素的组合引起的。APOL1在肾脏中的生物学功能和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）在与携带APOL1风险等位基因（HIV相关肾病）高度相关的CKD中提供对足细胞损失和肾小球硬化的保护的功能。这种保护的根本原因似乎与APOL 1 G0通过模式识别受体支持先天免疫信号传导事件的作用有关。此外，由于APOL1风险是一种复发性遗传特征，这也表明CKD可能部分由这种有益功能的丧失引起。为了推进这些研究，我们建议开发额外的基于细胞和基于动物的模型系统，以研究APOL 1 G0在先天免疫应答中的功能，以及在存在风险变体G1和G2的情况下这些应答如何改变。这些新的基于细胞和动物的系统将允许生化研究来解决作用机制和生理学研究来评估对CKD进展的影响，并应提供与APOL 1风险等位基因的隐性遗传相关的功能获得与功能丧失机制的见解。确定G0功能与风险变体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G0替代或风险变体抑制是否是更有效的策略。