The role of NFkB in calcineurin inhibitor-induced renal fibrosis

NFkB 在钙调神经磷酸酶抑制剂诱导的肾纤维化中的作用

• 批准号: 10463002
• 负责人: Adaku Ume
• 金额: $ 4.36万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463002
• 关键词: Address; Advocate; Applications Grants; Biological Assay; Calcineurin; Calcineurin inhibitor; Calmodulin; Catalytic Domain; Cell Survival; Cell physiology; Critical Thinking; Cyclosporine; Data; Development; Drug Screening; Drug toxicity; End stage renal failure; Event; Fibroblasts; Fibrosis; Future; Genes; Goals; I Kappa B-Alpha; Immune response; Immunity; Immunosuppression; Inflammatory; Injury; Injury to Kidney; Kidney; Kidney Failure; Kidney Transplantation; Knowledge; Lead; Lupus; Measures; Mediating; Mediator of activation protein; Methods; Molecular; Morphology; Mus; NF-kappa B; NF-kappaB-inducing kinase; Nephrology; Organ Transplantation; Outcome; PPP3CA gene; Pathogenesis; Pathway interactions; Patient Care; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phosphotransferases; Physiology; Plasmids; Process; Protein Isoforms; Proteins; Regulation; Renal function; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Tacrolimus; Testing; Therapeutic; Therapeutic immunosuppression; Tissues; Toxic effect; Transforming Growth Factor beta; Up-Regulation; Work; Writing; clinically relevant; experience; experimental study; improved; in vivo; inhibitor; inhibitor therapy; insight; interest; interstitial; kidney dysfunction; kidney fibrosis; mutant; nephrotoxicity; novel; post-transplant; prevent; renal damage; side effect; skills; success; transcription factor; virtual

Project Abstract/Summary Calcineurin inhibitors (CNIs) such as CsA and tacrolimus are vital immunosuppressive therapies in the management of inflammatory conditions such as post-transplantation immunosuppression, lupus nephritis46 and rare cases of atopic dermatitis47. Although CNIs have dramatically improved the quality of patient care, long-term therapy causes irreversible damage to the kidneys in the form of renal fibrosis. These morphologic changes ultimately lead to a decline in renal function and can progress to end-stage renal failure, a concern for both clinicians and patients. Therefore, the molecular mechanisms by which CNIs induce kidney damage need to be better understood, and to date, there are no specific therapeutic strategies to mitigate this injury. There exists therefore, a critical need to explain mechanisms by which CNIs promote renal damage. Interestingly, loss of CnAα activity in vivo increases markers of renal damage such as TGFβ and fibronectin3. It is currently unknown which signaling mediators promote the expression of renal damage markers upon loss of the CnAα isoform. Preliminary data show that exclusive loss of CnAα not only promotes expression of renal profibrotic markers but also induces NFκB activation. However, the next question, identifying whether these signaling changes occur via a common pathway, has not yet been answered. This grant proposal will address this gap in knowledge and test the hypothesis that renal CnAα inhibition upregulates NFκB signaling, which promotes irreversible renal damage. The expected project outcomes will characterize CnAα’s role in mediating renal damage through its regulation of NFκB. These findings will advocate and inspire future development of CnAα-sparing CNIs, ultimately circumventing the nephrotoxicity noted with long-term CNI use. To this end, this proposal seeks to I) determine whether NFκB activation promotes renal damage upon CnAα inhibition and II) determine how renal CnAα inhibition drives NFκB signaling. Successful completion of the proposed work will identify key mechanisms underlying the nephrotoxic effects of CNIs, thus informing future development of CnAα-sparing CNIs and/or additional therapies to counter these toxic effects. The long-term goal will be to mitigate the renal damage and dysfunction noted in patients placed on long-term CNI therapy.

项目摘要/摘要 钙调神经磷酸酶抑制剂（CNI）如CsA和他克莫司是免疫系统疾病中重要的免疫抑制疗法。 炎性疾病的管理，如移植后免疫抑制，狼疮性肾炎46和 特应性皮炎的罕见病例47.尽管CNI极大地提高了患者护理的质量，但长期而言， 治疗以肾纤维化的形式对肾造成不可逆的损害。这些形态学变化 最终导致肾功能下降，并可能进展为终末期肾衰竭，这是两种疾病的共同问题。 临床医生和患者。因此，CNI诱导肾损伤的分子机制需要进一步研究。 更好地理解，迄今为止，没有具体的治疗策略来减轻这种损伤。 因此，迫切需要解释CNI促进肾损伤的机制。 有趣的是，体内CnAα活性的丧失增加了肾损伤的标志物，如TGFβ和TGF β 2。 纤维连接蛋白3。目前尚不清楚哪些信号介质促进了肾损害的表达 CnAα亚型丢失后的标志物。初步数据表明，CnAα的完全缺失不仅促进了 表达肾促纤维化标记物，但也诱导NFκB活化。然而，下一个问题， 确定这些信号变化是否通过共同途径发生，尚未得到回答。这 一项拨款提案将填补这一知识空白，并检验肾CnAα抑制 上调NFκB信号传导，促进不可逆的肾损伤。项目预期成果 将描述CnAα通过调节NFκB介导肾损伤的作用。这些发现将 倡导并激励未来开发保留CnAα的CNI，最终避免肾毒性 注意到长期使用CNI。 为此，该建议旨在I）确定NFκB活化是否促进肾损伤， CnAα抑制和II）确定肾CnAα抑制如何驱动NFκB信号传导。成功完成 拟议的工作将确定CNI肾毒性作用的关键机制，从而为未来的研究提供信息。 开发保留CnAα的CNI和/或其他治疗以对抗这些毒性作用。远景目标 将减轻接受长期CNI治疗的患者中观察到的肾损伤和功能障碍。