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Cellular and Molecular Response to Gentamicin-Induced Injury in Underdeveloped Kidneys

发育不全的肾脏对庆大霉素引起的损伤的细胞和分子反应

基本信息

批准号：
10591824
负责人：
Pamela Isabel Good
金额：
$ 16.7万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2023-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591824
关键词：
Acceleration Acute Acute Renal Failure with Renal Papillary Necrosis Adult Animal Model Apoptosis Binding Brush Border CCL2 gene CXCL10 gene Cell Death Cells Cellular Metabolic Process Cessation of life Chronic Chronic Kidney Failure Clinical Research DNA Dedications Development Disease Distal Duct (organ) structure Endocytosis Endowment Environment Exposure to Fellowship Future Gentamicins Gestational Age Goals Growth Growth and Development function Health Human Impairment Inflammation Inflammatory Inflammatory Response Injury Injury to Kidney Institution Kidney Kidney Diseases Link LoxP-flanked allele Lysosomes Measures Mentors Metanephric Diverticulum Mitochondria Modeling Molecular Molecular Target Morphology Mus Names Necrosis Neonatal Nephrons Pathogenesis Pathogenicity Pathway Analysis Pathway interactions Pediatrics Pharmaceutical Preparations Physicians Play Population Positioning Attribute Pregnancy Premature Infant Prevention strategy Process Production RIPK3 gene Research Risk Role Rupture Scientist Signal Transduction System Testing Tetanus Helper Peptide Toxic effect Training Tubular formation Universities career career development cell injury clinical training clinically relevant critical period cytokine design disease phenotype exposed human population human model improved inhibitor kidney biopsy knowledge base mouse model neonatal human nephrogenesis nephrotoxicity novel postnatal postnatal period premature prevent professor programs pup response single-cell RNA sequencing skills targeted treatment treatment strategy uptake

项目摘要

PROJECT SUMMARY Humans born before 34-36 weeks of gestation age have low nephron endowment and a 2-3-fold increased risk of chronic kidney disease (CKD). Preterm infants are also at increased risk of acute kidney injury (AKI), which is a unique pathogenic process as injury occurs during a critical window of postnatal renal growth and maturation. However, due to limited animal models and few preterm human kidney biopsies, the cellular and molecular basis of AKI and CKD in premature kidneys is poorly understood, treatment is supportive, and we lack strategies to prevent AKI and the development of CKD in this population. We have generated a novel mouse model of congenitally low nephron number that simulates human premature kidneys and propose a 5-year career development project that is designed to fill the unmet needs. I induced neonatal AKI with gentamicin, a nephrotoxic medication often prescribed to preterm infants, and discovered that mice with low nephron number have more severe AKI, sustained inflammation and rapid progression to CKD compared to littermate controls with normal nephron number. I have also identified a unique inflammatory profile following gentamicin-induced AKI in mice with low nephron number. I hypothesize that increased gentamicin uptake in proximal tubules of mice with low nephron number leads to more cell injury and death, causing profound and sustained inflammation, impairing renal growth, and accelerating the development of CKD. Aim 1 will determine the cellular basis for more severe gentamicin-induced injury and inflammation by assessing for increased gentamicin uptake and accumulation, and then by determining whether gentamicin accumulation causes lysosomal and mitochondrial damage and resultant inflammation. We will determine which cell death pathways are activated after gentamicin- induced injury in mice with low nephron number, the discovery of which could inform future targeted therapies. In Aim 2 we will study the effect of gentamicin-induced renal inflammation on renal growth and the development of CKD in mice with low nephron number. We will take the unbiased approach of single cell RNA sequencing and analyze pathways regulating cell metabolism, growth, inflammation, and cell death in mice with normal and low nephron number after acute injury, and during a critical period of postnatal renal growth and maturation. The discovery-based studies have the potential to guide future molecular targeting approaches to abrogate the development of CKD in humans born preterm. The career development strategy proposed will allow Dr. Good to acquire the training necessary to become a successful physician scientist studying the cellular and molecular basis of renal health and disease in a growing population of humans born preterm. Dr. Good is a neonatologist and Assistant Professor of Pediatrics at Columbia University, where she completed her clinical training and research fellowship. With the support of a rich institutional environment and the dedication of her mentors, Drs. Fangming Lin and Jonathan Barasch, Dr. Good will be well positioned to transition to independence.

项目总结