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Ferroptosis and Ferroptotic Stress in Maladaptive Renal Repair

适应不良肾修复中的铁死亡和铁死亡应激

基本信息

批准号：
10655821
负责人：
Tomokazu Souma
金额：
$ 52.38万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655821
关键词：
Acceleration Acute Acute Renal Failure with Renal Papillary Necrosis Affect Attenuated COVID-19 Cardiovascular system Cell Culture Techniques Cell Death Cell membrane Cells Cessation of life Chronic Chronic Kidney Failure Clinical Data Dependence Development Dialysis procedure Disease Doxycycline ESR1 gene Environment Estrogen Receptors Estrogens Event Exhibits Female Fibrosis GPER gene Genetic Gonadal Steroid Hormones Health Histopathology Hormonal Hospitalization Human Immune Immune response Impairment In Vitro Inflammation Inflammatory Injury to Kidney Interruption Investigation Ischemia Kidney Knockout Mice Knowledge Lipid Peroxidation Lipid Peroxides Longitudinal Studies LoxP-flanked allele Modeling Molecular Mus Mutant Strains Mice Operative Surgical Procedures Organ Organoids Outcome Ovariectomy Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Pharmacology Study Phenotype Predisposition Process Receptor Signaling Recovery Reduced Glutathione Regulation Regulatory Pathway Renal function Reperfusion Injury Research Residual state Resolution Risk Rupture Sex Differences Stress Tamoxifen Testing Testosterone Therapeutic Effect Transcription Alteration Tubular formation design early experience epithelial injury female sex hormone glutathione peroxidase high risk improved in vivo Model induced pluripotent stem cell inhibitor injury recovery insight ischemic injury kidney fibrosis kidney repair male mortality mouse genetics mouse model new therapeutic target novel novel therapeutics pharmacologic pre-clinical prevent repaired resilience response sex sexual dimorphism stress resilience targeted treatment transcriptomics

项目摘要

PROJECT SUMMARY Acute kidney injury (AKI) is a major health problem, afflicting 1.2 million hospitalized patients annually in the US. Maladaptive renal repair after AKI promotes development of chronic kidney disease (CKD), leaving affected patients at high risk for dialysis dependency, cardiovascular events, and mortality. Studies show that males are disproportionately and more severely affected by AKI than females, including COVID-19-associated AKI. However, the molecular mechanisms underlying this sexual dimorphism remain poorly understood. Moreover, there are no targeted therapies that interrupt this devastating disease process in both sexes. Using single-cell transcriptomics and mouse genetics, our ongoing studies found that the female sex confers marked protection against ferroptosis, a distinct, non-apoptotic form of regulated cell death and a critical driver of maladaptive repair after AKI in mice and humans. Ferroptosis is triggered by the inability of glutathione peroxidase 4 (GPX4) to remove toxic lipid peroxides from cell membranes, leading to the accelerated accumulation of toxic lipid peroxides (ferroptotic stress) and cell rupture. Acute ischemic and toxic kidney injuries reduce GPX4 in proximal tubular (PT) cells, thus making these cells vulnerable to ferroptosis. Severe AKI also induces pathologic transcriptional alteration of PT cells into an inflammatory phenotype and prevents their recovery to a healthy state (impaired plasticity). Our data show that in males but not in females, genetic deletion of Gpx4 promotes the accumulation of inflammatory PT cells and triggers their death by ferroptosis. To advance these clinically impactful lines of investigation, we will test our overarching hypothesis that sexual dimorphism in resilience to ferroptosis underlies sex differences in clinical outcomes after AKI. We further hypothesize that uncovering the mechanisms of how sex hormones regulate ferroptosis sensitivity will enable identification of targetable downstream pathways that improve AKI outcomes for both sexes. Directly testing these hypotheses, we will integrate unbiased single-cell transcriptomics, genetic mouse models, pharmacological studies, and human kidney organoids with two Specific Aims. In Aim 1, we will determine sex-dependent mechanisms by which ferroptosis promotes maladaptive repair at single-cell resolution using our tubule-specific, doxycycline-inducible Gpx4 knockout mouse model. We will also investigate the therapeutic effects of ferroptosis inhibitors to enhance renal repair in our murine kidney injury models in vivo and in human in vitro AKI models using organoids. In Aim 2, we will test our hypothesis that sex hormones regulate the sensitivity to ferroptosis and PT cell plasticity after AKI using gonadectomy and genetic inhibition of estrogen receptor signaling. The results of these studies will provide compelling preclinical mechanistic evidence for how ferroptotic stress governs PT cell fate. Our studies will identify new therapeutic targets to enhance renal ferroptotic stress resilience and promote healthy PT recovery from injury, thereby interrupting the AKI to CKD transition in both sexes.

项目总结