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/总结 钙调神经磷酸酶抑制剂 (CNI)，例如 CsA 和他克莫司，是重要的免疫抑制疗法 炎症性疾病的管理，例如移植后免疫抑制、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质量，但长期来看 治疗会以肾纤维化的形式对肾脏造成不可逆的损害。这些形态变化 最终导致肾功能下降，并可能进展为终末期肾衰竭，这是双方都关心的问题 临床医生和患者。因此，需要进一步了解 CNI 诱导肾损伤的分子机制。 更好地理解，迄今为止，还没有减轻这种损伤的具体治疗策略。 因此，迫切需要解释 CNI 促进肾损伤的机制。 有趣的是，体内 CnAα 活性的丧失会增加肾损伤标志物，例如 TGFβ 和 纤连蛋白3.目前尚不清楚哪些信号介质促进肾损伤的表达 CnAα 同种型丢失时的标记。初步数据表明，CnAα 的排他性丢失不仅促进 肾促纤维化标志物的表达，还诱导 NFκB 激活。然而，下一个问题， 确定这些信号传导变化是否通过共同途径发生尚未得到解答。这 拨款提案将解决这一知识空白并检验肾脏 CnAα 抑制的假设 上调 NFκB 信号传导，从而促进不可逆的肾损伤。预期项目成果 将表征 CnAα 通过调节 NFκB 在介导肾损伤中的作用。这些发现将 倡导并激励保留 CnAα 的 CNI 的未来发展，最终避免肾毒性 长期使用 CNI 会引起注意。 为此，本提案旨在 I) 确定 NFκB 激活是否会促进肾损伤 CnAα 抑制和 II) 确定肾 CnAα 抑制如何驱动 NFκB 信号传导。圆满完成了 拟议的工作将确定 CNI 肾毒性作用的关键机制，从而为未来提供信息 开发保留 CnAα 的 CNI 和/或其他疗法来对抗这些毒性作用。长期目标 将减轻长期 CNI 治疗患者出现的肾损伤和功能障碍。