The gene regulatory landscape of healthy and failed repair proximal tubule subpopulations in kidney disease

肾脏疾病中健康和修复失败的近端小管亚群的基因调控景观

• 批准号: 10599152
• 负责人: Nicolas Hyun Ledru
• 金额: $ 5.16万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599152
• 关键词: ATAC-seq; Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; Affect; Aging; American; Area; Back; Binding; Bioinformatics; Black, Indigenous, People of Color; Cell Culture Techniques; Cell Nucleus; Cells; Characteristics; Chromatin; Chronic; Chronic Kidney Failure; Clinical; Data Set; Development; Dialysis procedure; Disease; Disease Outcome; Disease Progression; End stage renal failure; Environment; Epigenetic Process; Fibrosis; Financial Hardship; Gene Expression Profile; Generations; Genetic; Genetic Transcription; Goals; Health; Healthcare; Heterogeneity; Human; In Vitro; Incentives; Individual; Inflammatory; Injury to Kidney; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Laboratories; Learning; Libraries; Life; Maintenance; Mediating; Medical; Modeling; Multiomic Data; Nucleic Acid Regulatory Sequences; Organ; Outcome; Patients; Persons; Phenotype; Physicians; Population; Prevalence; Profibrotic signal; Recovery; Regulator Genes; Regulatory Element; Renal Replacement Therapy; Renal function; Research; Resolution; Role; Sampling; Scientist; Signal Transduction; Techniques; Therapeutic; Therapeutically Targetable; Training; Update; Validation; Work; burden of illness; candidate identification; career; cell type; collaborative environment; computerized tools; educational atmosphere; effective therapy; experience; gene regulatory network; health disparity; improved; injury and repair; insight; multimodality; multiple omics; network models; patient population; repaired; risk variant; single cell sequencing; single nucleus RNA-sequencing; single-cell RNA sequencing; therapeutic candidate; transcription factor; transcriptome; transcriptomics; treatment strategy

Chronic kidney disease (CKD) has an immense burden on healthcare, with a prevalence of 37 million in the American population. Untreated CKD leads to fibrosis and declining renal function until a patient requires life- sustaining renal replacement therapy, so there is a critical need for treatment options to halt or reverse the progression of disease. My lab has characterized a pro-inflammatory cell type, originating from the failed repair of injured proximal tubule (FR-PT) cells, that correlates with failed recovery from acute kidney injury (AKI) and subsequent transition to CKD. Single cell RNA and ATAC sequencing of human adult kidney samples has provided evidence for this cell state’s presence in kidneys that have not experienced AKI. As such the FR-PT cell could represent a convergence point for acute and chronic renal injury through which progressive inflammatory and fibrotic signals are perpetuated, leading to CKD progression. A treatment that inhibits or reverses transition to a failed repair state could ameliorate CKD outcomes by reducing the FR-PT cell population responsible for continued pro-inflammatory and pro-fibrotic signaling. Since FR-PT cells appear to be a distinct population from healthy proximal tubule (PT) cells, gene regulatory mechanisms may be an important contributing factor to the formation of FR-PT cells. This project will reveal the gene regulatory networks and regulatory elements underpinning development of the FR-PT cell population through analysis of a single cell multiomic dataset generated by integrating single cell RNA-seq and ATAC-seq profiles of adult human kidney, specifically focusing on characterizing transcriptional and epigenetic differences between healthy PT and FR-PT cells. This dataset will be used to train a parametric gene regulatory network model for PT cells to identify candidate cis- and trans-regulatory elements involved in the transition between healthy and failed repair PT states. This will be followed by experimental validation of the identified regulatory elements to confirm their predicted role. This proposal aims to identify therapeutic candidates targeting FR-PT cells as a driver of CKD progression, addressing an outstanding need for better CKD therapies. Completion of this project will also help me achieve my training goals to expand my scientific knowledge, learn to identify and study translatable research questions, and gain experience with bioinformatics and single cell techniques. Dr. Benjamin Humphreys is a model physician-scientist for these goals, and his laboratory is an optimal environment for this project and my training goals, because of his research group’s single cell expertise and the lab’s excellent training and collaborative atmosphere. Successful completion of this project will contribute a better understanding of CKD and possible treatment strategies and will prepare me to pursue a career as an independent physician-scientist.

慢性肾脏疾病（CKD）对医疗保健有着巨大的负担，在美国有3700万的患病率