Targeting ferroptosis in renal tubular epithelial cells to improve outcomes of lupus nephritis

靶向肾小管上皮细胞铁死亡以改善狼疮性肾炎的预后

基本信息

  • 批准号:
    10638468
  • 负责人:
  • 金额:
    $ 49.31万
  • 依托单位:
  • 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:
    2023-04-01 至 2028-01-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Lupus nephritis is one of the most severe end-organ manifestations of systemic lupus erythematosus. Immunosuppression, the cornerstone for treating this disease, is complicated by many adverse effects. Although traditionally considered as a glomerular disease, up to 80% of lupus nephritis patients present with tubular injury, and tubular injury is a better predictor of progression to end stage kidney disease than glomerular injury. This identifies the renal tubules as a therapeutic target in lupus nephritis. The complex biological mechanisms that underlie tubular epithelial cell injury in lupus nephritis remain, for the most part, obscure. We propose to provide such a mechanistic understanding by leveraging our key novel findings. We have shown that iron accumulates in the tubular compartment of the lupus nephritis kidneys but not in the glomeruli. Most of the iron recycling in the kidney is performed by proximal tubular epithelial cells, and excess iron induces ferroptosis -- an inflammatory form of cell death characterized by high levels of lipid peroxidation. Ferroptosis is mostly observed in the tubular segments of human and murine lupus nephritis kidneys. We have found that the enzyme Acyl-CoA synthetase long-chain family member 4 (ACSL4), a ferroptosis promoter, was increased whereas SLC7A11, a ferroptosis inhibitor, was decreased in lupus nephritis. Additionally, human lupus nephritis serum induced ferroptosis in proximal tubular epithelial cells and this was associated with inflammation and injury. Liproxstain-2, a novel ferroptosis inhibitor, blocked these outcomes. These data led us to hypothesize that iron accumulation in proximal tubular epithelial cells promotes ferroptosis, propagates tubulointerstitial inflammation and worsens outcomes of lupus nephritis. We aim to test this hypothesis using congenic mice deficient for ACSL4 (Acsl4PTEC-/-) and SCL7A11 (Slc7a11PTEC-/-) only in their proximal tubular epithelial cells (PTEC). We will first investigate the resistance of Acsl4PTEC-/- and susceptibility of Slc7a11PTEC-/- mice to ferroptosis using an inducible and a spontaneous mouse model of immune complex glomerulonephritis, identify the downstream molecular pathways that block or lead to ferroptosis and follow the outcomes of kidney injury. Using lupus nephritis patients and healthy controls, we will dissect the ferroptosis inducing ability of whole and immunoglobin depleted serum on proximal tubular epithelial cells as well as test novel ACSL4 inhibitors. Using purified cells from the same cohort of patients and controls we will block known repressors of SLC7A11 and evaluate outcomes of ferroptosis and tubular pathology. Finally, we will evaluate the in vivo therapeutic efficacy of Liproxstain-2 in two spontaneous murine models of lupus nephritis with existing renal injury. These studies will identify novel mechanisms of proximal tubular epithelial cell injury in lupus nephritis and support use of ferroptosis inhibitors as a novel adjunct therapy to reduce dependency on traditional immunosuppressants.
项目总结/文摘

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Laurence Morel其他文献

Laurence Morel的其他文献

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{{ truncateString('Laurence Morel', 18)}}的其他基金

Determinants of follicular helper T cell expansion in lupus
狼疮滤泡辅助 T 细胞扩张的决定因素
  • 批准号:
    10644534
  • 财政年份:
    2022
  • 资助金额:
    $ 49.31万
  • 项目类别:
Determinants of follicular helper T cell expansion in lupus
狼疮滤泡辅助 T 细胞扩张的决定因素
  • 批准号:
    10679012
  • 财政年份:
    2022
  • 资助金额:
    $ 49.31万
  • 项目类别:
Determinants of follicular helper T cell expansion in lupus
狼疮滤泡辅助 T 细胞扩张的决定因素
  • 批准号:
    10065726
  • 财政年份:
    2020
  • 资助金额:
    $ 49.31万
  • 项目类别:
Determinants of follicular helper T cell expansion in lupus
狼疮滤泡辅助 T 细胞扩张的决定因素
  • 批准号:
    10212953
  • 财政年份:
    2020
  • 资助金额:
    $ 49.31万
  • 项目类别:
Gut dysbiosis and tryptophan metabolism in lupus
狼疮中的肠道菌群失调和色氨酸代谢
  • 批准号:
    10079461
  • 财政年份:
    2019
  • 资助金额:
    $ 49.31万
  • 项目类别:
Gut dysbiosis and tryptophan metabolism in lupus
狼疮中的肠道菌群失调和色氨酸代谢
  • 批准号:
    10543063
  • 财政年份:
    2019
  • 资助金额:
    $ 49.31万
  • 项目类别:
Gut dysbiosis and tryptophan metabolism in lupus
狼疮中的肠道菌群失调和色氨酸代谢
  • 批准号:
    10321633
  • 财政年份:
    2019
  • 资助金额:
    $ 49.31万
  • 项目类别:
Gut dysbiosis and tryptophan metabolism in lupus
狼疮中的肠道菌群失调和色氨酸代谢
  • 批准号:
    10675349
  • 财政年份:
    2019
  • 资助金额:
    $ 49.31万
  • 项目类别:
Gut dysbiosis induces lupus
肠道菌群失调诱发狼疮
  • 批准号:
    9199844
  • 财政年份:
    2016
  • 资助金额:
    $ 49.31万
  • 项目类别:
Targeting follicular helper CD4 T cells in SLE
靶向 SLE 中的滤泡辅助 CD4 T 细胞
  • 批准号:
    10667605
  • 财政年份:
    2016
  • 资助金额:
    $ 49.31万
  • 项目类别:

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