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:
    10383979
  • 负责人:
  • 金额:
    $ 56.49万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-23 至 2026-05-31
  • 项目状态:
    未结题

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 (a gene-environment interaction). Despite the association of CKD risk with APOL1 variants more than ten years ago, the biological function of APOL1 in the kidney and the mechanism of pathogenesis in the setting of a disease stressor remain unclear. Our long-term goal is to understand the genetics and biochemical mechanism of CKD in African Americans caused by these APOL1 polymorphisms. To accomplish this goal, we are studying HIV-associated nephropathy (HIVAN), the CKD most strongly associated APOL1 variants, and the only CKD where the environmental stressor is known (HIV infection). HIVAN is an ideal disease model to dissect biochemical pathways and cellular events intersected by APOL1 function, viral infection, and CKD. 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 in HIVAN. Since APOL1 risk is a recessively inherited trait, this suggests CKD may be caused, in part, by a loss-of-function process (i.e. absence of G0). In new preliminary data, G0 appears to associate with Toll-like receptors (TLRs) in intracellular vesicles containing HIV and facilitate signaling events initiated by interferon regulatory factor (IRF)-3, and these processes were absent with the APOL1 risk variants. Methods will use established in vitro HIV infection of human podocyte cell lines, in vivo models of HIVAN and BAC-APOL1 transgenic mice that replicate endogenous human APOL1 expression. Aims will examine both initial response to HIV infection in podocytes, and long-term in vivo studies of intercrosses between the HIVAN and BAC-APOL1 transgenic mice evaluating effects on renal function and pathology. These studies also will establish temporal and magnitude of stressor-induced APOL1 expression, the mechanism of the altered innate immune activation through TLRs to IRF-3/7 signaling, and effect on podocyte phenotype (survival and cell adhesion). The dominance of the G0 protective effect over the risk variant dysfunction will be tested in podocytes and mouse models co-expressing G0 and the risk variants. These studies should advance our understanding of gain- versus loss-of-function mechanism associated with the recessive inheritance of APOL1 risk alleles, and the necessity of induced APOL1 expression to drive stress responses. 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

项目成果

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Leslie A Bruggeman其他文献

Leslie A Bruggeman的其他文献

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{{ truncateString('Leslie A Bruggeman', 18)}}的其他基金

Mechanisms of Kidney Diseases Associated With APOL1 Variation
APOL1 变异相关肾脏疾病的机制
  • 批准号:
    10607630
  • 财政年份:
    2023
  • 资助金额:
    $ 56.49万
  • 项目类别:
Intracellular functions of APOL1 in the kidney
APOL1 在肾脏中的细胞内功能
  • 批准号:
    10493392
  • 财政年份:
    2021
  • 资助金额:
    $ 56.49万
  • 项目类别:
Intracellular functions of APOL1 in the kidney
APOL1 在肾脏中的细胞内功能
  • 批准号:
    10666584
  • 财政年份:
    2021
  • 资助金额:
    $ 56.49万
  • 项目类别:
Intracellular functions of APOL1 in the kidney
APOL1 在肾脏中的细胞内功能
  • 批准号:
    10252083
  • 财政年份:
    2020
  • 资助金额:
    $ 56.49万
  • 项目类别:
Mechanisms of APOL1-mediated kidney disease
APOL1 介导的肾脏疾病的机制
  • 批准号:
    9146894
  • 财政年份:
    2015
  • 资助金额:
    $ 56.49万
  • 项目类别:
Mechanisms of APOL1-mediated kidney disease
APOL1 介导的肾脏疾病的机制
  • 批准号:
    9319750
  • 财政年份:
    2015
  • 资助金额:
    $ 56.49万
  • 项目类别:
Kidney disease mechanisms associated with human genetic variation
与人类遗传变异相关的肾脏疾病机制
  • 批准号:
    9284462
  • 财政年份:
    2014
  • 资助金额:
    $ 56.49万
  • 项目类别:
Kidney disease mechanisms associated with human genetic variation
与人类遗传变异相关的肾脏疾病机制
  • 批准号:
    8642932
  • 财政年份:
    2014
  • 资助金额:
    $ 56.49万
  • 项目类别:
Kidney disease mechanisms associated with human genetic variation
与人类遗传变异相关的肾脏疾病机制
  • 批准号:
    9653298
  • 财政年份:
    2014
  • 资助金额:
    $ 56.49万
  • 项目类别:
Cell junction proteins in podocyte injury repair
足细胞损伤修复中的细胞连接蛋白
  • 批准号:
    8342329
  • 财政年份:
    2012
  • 资助金额:
    $ 56.49万
  • 项目类别:

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