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：
10373167
负责人：
Santhakumar Manicassamy
金额：
$ 23.1万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373167
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.

摘要：白色念珠菌感染是住院患者的第三大常见感染，死亡率范围在14.5％–49％之间。传播念珠菌病导致肾衰竭导致免疫功能低下的宿主的严重发病率，例如患有免疫缺陷综合征的宿主或癌症，器官或骨髓移植患者或服用免疫抑制药物的患者延长一段时间。预防和治疗传播的念珠菌病是一个重要的临床问题，并且目前，尚无针对任何真菌病原体的批准疫苗。但是，细胞和分子由病原念珠菌感染引起的肾衰竭的机制仍然很大未知。免疫系统在防止传播念珠菌病中起着重要作用。免疫激活肾脏抗原细胞（APC）中的途径在诱导的强大免疫反应中起关键作用针对白色念珠菌的肾脏。相反，APC中的抗炎途径抑制免疫肾脏对白色念珠菌的反应以及增加对肾脏损伤和失败的敏感性。那，识别针对免疫原性与调节状态编程的信号通路将有助于确定增强肾脏免疫力的免疫细胞热操作的新目标防止白色念珠菌，并防止与感染相关的kidney损害和失败。我们有确定了β-catenin和TCF4的新的且先前未刺的作用，为关键分子抗炎 APC中的途径对于抑制免疫反应至关重要增加了对肾脏损伤和失败的敏感性。该应用旨在描绘分子 β-catenin和TCF4代谢肾脏APC针对传播的机制念珠菌病及其对肾功能的影响。