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Regulation of acute kidney injury to Candida albicans by b-catenin/TCF pathway

b-catenin/TCF通路调控白色念珠菌急性肾损伤

基本信息

批准号：
10495218
负责人：
Santhakumar Manicassamy
金额：
$ 19.25万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10495218
关键词：
Acquired Immunodeficiency Syndrome Acute Renal Failure with Renal Papillary Necrosis Anti-Inflammatory Agents Antigen-Presenting Cells Bone Marrow Transplantation Candida albicans Cell Differentiation process Cells Clinical Data Dendritic Cells Disseminated candidiasis Epithelial Cells Felis catus Genetic Transcription Immune Immune response Immune system Immunity Immunocompromised Host Immunosuppressive Agents In Vitro Infection Inflammasome Inflammatory Response Injury Injury to Kidney Innate Immune Response Kidney Kidney Failure Knockout Mice Link MAP Kinase Gene Malignant Neoplasms Mediating Mediator of activation protein Metabolic Metabolic Pathway Modeling Molecular Morbidity - disease rate Organ Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Pharmacology Play Predisposition Prevention Reagent Regulation Regulatory Pathway Renal function Role Shapes Signal Pathway Signal Transduction TCF7L2 gene Testing Therapeutic Time Transplant Recipients Tubular formation Vaccines adaptive immune response antimicrobial peptide beta catenin conditional knockout immunogenic in vivo kidney infection macrophage mortality new therapeutic target pathogenic fungus programs renal damage response transcription factor

项目摘要

Summary: Candida albicans infection is the third most common infection in hospitalized patients, with a mortality rate ranging between 14.5%–49%. Disseminated candidiasis causes kidney failure resulting in severe morbidity of the immunocompromised host such as those with acquired immune deficiency syndrome or cancer, organ or bone marrow transplant patients, or patients taking immunosuppressant drugs an extended period of time. Prevention and treatment of disseminated candidiasis are an important clinical problem, and currently, there are no approved vaccines against any fungal pathogens. However, the cellular and molecular mechanisms underlying renal failure caused by pathogenic Candida albicans infection remain largely unknown. The immune system plays an important role in protecting against disseminated candidiasis. Immune activating pathways in renal antigen-presenting cells (APCs) play a critical role in inducing robust immune responses in the kidney against C. albicans. In contrast, the anti-inflammatory pathways in APCs suppress immune responses in the kidney against C. albicans and increasing susceptibility to kidney damage and failure. Thus, identifying the signaling pathways that program APCs towards an immunogenic state versus a regulatory state will help identify new targets for therapeutic manipulation of immune cells that augments kidney immunity against Candida albicans and protects against infection-associated-kidney damage and failure. We have identified a new and previously unsuspected role for β-catenin and TCF4 as a key molecular anti-inflammatory pathway in APCs that is critical for suppressing immune responses against disseminated candidiasis, causing increased susceptibility to kidney damage and failure. This application aims to delineate the molecular mechanisms by which β-catenin and TCF4 metabolically program renal APCs against disseminated candidiasis and its impact on kidney function.

总结：白色念珠菌感染是住院患者第三常见的感染，其中死亡率在14.5%-49%之间。播散性念珠菌病导致肾衰竭，免疫功能低下宿主的严重发病率，如患有获得性免疫缺陷综合征的宿主或癌症、器官或骨髓移植患者，或长期服用免疫抑制药物的患者，段时间播散性念珠菌病的预防和治疗是一个重要的临床问题，目前还没有针对任何真菌病原体的批准疫苗。然而，细胞和分子致病性白色念珠菌感染引起的肾衰竭的潜在机制在很大程度上仍然未知。免疫系统在预防播散性念珠菌病方面起着重要作用。免疫活化肾抗原呈递细胞（APC）中的免疫通路在诱导免疫应答中起着关键作用。肾脏对C.白色念珠菌相反，APC中的抗炎通路抑制免疫反应。肾脏对C.白色念珠菌和增加对肾损伤和衰竭的易感性。因此，在本发明中，鉴定将APC编程为免疫原性状态相对于调节状态的信号通路将有助于确定新的目标，用于增强肾脏免疫力的免疫细胞的治疗操作抗白色念珠菌，并防止感染相关的肾损伤和衰竭。我们有确定了β-连环蛋白和TCF 4作为关键的抗炎分子的一种新的和以前未被怀疑的作用， APCs中的途径，对于抑制针对播散性念珠菌病的免疫应答至关重要，增加对肾损伤和衰竭的易感性。本申请旨在描述分子生物学中的 β-连环蛋白和TCF 4代谢编程肾APC对抗播散性念珠菌病及其对肾功能的影响。