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: 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
• 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

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