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

基本信息

批准号：
10700842
负责人：
Adaku Ume
金额：
$ 4.51万
依托单位：
WRIGHT STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10700842
关键词：
Advocate Applications Grants Atopic Dermatitis Biological Assay Calcineurin Calcineurin inhibitor Calmodulin Catalytic Domain Cell Survival Cell physiology Communication Complex Critical Thinking Cyclosporine Data Development Drug Screening Drug toxicity End stage renal failure Event Fibroblasts Fibronectins Fibrosis Future Genes Goals Immune response Immunity Immunosuppression Inflammatory Injury Injury to Kidney Kidney Kidney Failure Kidney Transplantation Knowledge Lupus Nephritis Measures Mediating Mediator 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 Phosphorylation Phosphotransferases Physiology Plasmids Process Protein Dephosphorylation 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 cortex kidney dysfunction kidney fibrosis mutant nephrotoxicity novel pharmacologic post-transplant prevent renal damage side effect skills success transcription factor virtual

项目摘要

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和尽管 CNI 显着提高了患者护理质量，但从长远来看，特应性皮炎的罕见病例47。治疗会以肾纤维化的形式对肾脏造成不可逆的损害。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。这意味着，体内 CnAα 活性的丧失会增加肾损伤标志物，例如 TGFβ 和目前尚不清楚哪些信号介质促进肾损伤的表达。初步数据显示，CnAα 亚型丢失后的标记物不仅会促进 CnAα 丢失。肾脏促纤维化标志物的表达还诱导 NFκB 激活然而，下一个问题是，确定这些信号变化是否通过共同途径发生，尚未得到解答。拨款提案将解决这一知识空白并检验肾 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的项目结果。这些发现将表征 CnAα 通过调节 NFκB 在介导肾损伤中的作用。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 信号传导的成功完成。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是长期目标。将减轻长期 CNI 治疗患者出现的肾损伤和功能障碍。