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
- 来源:
- 关键词:Adverse effectsAnimalsAntibodiesAntigen-Antibody ComplexAttenuatedAutoantibodiesBiologicalBone MarrowCD4 Positive T LymphocytesCell DeathCell surfaceCellsChimera organismCoenzyme A LigasesComplexCongenic MiceCystineDataDependenceDepositionDiseaseDoseEnd stage renal failureEnzymesEpithelial CellsEtiologyExposure toFamilyFamily memberFoundationsGenerationsGenesGenetic TranscriptionGlomerulonephritisGlutathioneHumanImmune Complex GlomerulonephritisImmunoglobulin GImmunoglobulinsImmunosuppressionImmunosuppressive AgentsImpairmentInflammationInflammatoryInjuryInjury to KidneyIronKidneyKidney FailureLeadLipid PeroxidationLoxP-flanked alleleLupusLupus NephritisMediatingMedicalModelingMolecularMusNephritisOrganOutcomePathologyPathway interactionsPatientsPolyunsaturated Fatty AcidsPredispositionProteinuriaRecyclingRenal glomerular diseaseRenal tubule structureResistanceSamplingSerumSortingSystemSystemic Lupus ErythematosusTestingTherapeuticTreatment EfficacyTubular formationcell injurycohortdesignimproved outcomein vivoinhibitorkidney epithelial celllipidomicslupus prone micemRNA Precursormembermouse modelnephrotoxicityneutralizing antibodynew therapeutic targetnovelnovel strategiesoxidationpromoterprotein biomarkerssolutetherapeutic targetuptake
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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科研奖励数量(0)
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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:
Targeting follicular helper CD4 T cells in SLE
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- 批准号:
10667605 - 财政年份:2016
- 资助金额:
$ 49.31万 - 项目类别:
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