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 钙调蛋白抑制剂（CNIS），例如CSA和他克莫司，是至关重要的免疫抑制疗法 治疗炎症状况，例如移植后免疫抑制，狼疮肾炎46和 罕见的特应性皮炎病例47.尽管CNIS极大地提高了患者护理的质量，但长期 治疗会以肾纤维化形式对孩子造成不可逆转的损害。这些形态学的变化 最终导致肾功能下降，并可以发展为终末期肾衰竭，这是两者的关注 临床医生和患者。因此，CNIS诱导肾脏损伤的分子机制是 更好地理解，迄今为止，还没有具体的治疗策略来减轻这种伤害。 因此，存在着解释CNIS促进肾脏损害的机制的迫切需要。 有趣的是，体内CNAα活性的丧失会增加肾脏损伤的标志物，例如TGFβ和 Fibronectin3。目前尚不清楚哪个信号传导介质促进肾脏损伤的表达 丢失CNAα同工型的标记。初步数据表明，CNAα的独家损失不仅促进 肾脏纤维化标记的表达，但也诱导NFκB激活。但是，下一个问题， 确定这些信号变化是否通过通用途径发生，尚未回答。这 赠款提案将在知识上解决这一差距，并检验肾脏CNAα的假设 上调NFκB信号传导，从而促进不可逆的肾脏损伤。预期的项目成果 将表征CNAα通过调节NFκB在介导肾脏损伤中的作用。这些发现会 倡导和启发CNAα比CNIS的未来发展，最终避免了肾毒性 长期使用CNI使用。 为此，该提案寻求i）确定NFκB激活是否会促进肾脏损害 CNAα抑制和ii）确定肾脏CNAα抑制如何驱动NFκB信号传导。成功完成 拟议的工作将确定CNIS肾毒性作用的基础的关键机制，从而告知未来 开发CNAα的CNIS和/或其他疗法以应对这些毒性作用。长期目标 将减轻接受长期CNI治疗的患者所指出的肾脏损伤和功能障碍。