Defining The Role of Failed-Repair Proximal Tubule Cells in AdvancedRenal Disease in African Americans

确定修复失败的近端小管细胞在非裔美国人晚期肾病中的作用

• 批准号: 10740665
• 负责人: Shayna Toyan Joy Bradford
• 金额: $ 9.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740665
• 关键词: Ablation; Acceleration; Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Adopted; Advisory Committees; African American; African American population; African ancestry; Age; American; Area; Award; Biology; Biomedical Research; Cell Differentiation process; Cell Line; Cells; Cellular biology; Chronic Kidney Failure; Communities; Data; Development Plans; Diabetes Mellitus; Disease; Disease Outcome; Disparity; Doctor of Philosophy; Down-Regulation; End stage renal failure; Epithelial Cells; European; Event; Faculty; Fibrosis; Foundations; Genes; Genetic; Goals; HNF4A gene; Health; Human; Hypertension; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Interferon Type I; Kidney; Kidney Diseases; Knowledge; LoxP-flanked allele; MAP4K4 gene; Mediator; Molecular; Molecular Profiling; Mus; Natural regeneration; Nephrons; Persons; Phase; Phenotype; Phosphotransferases; Physicians; Population; Prevalence; Proximal Kidney Tubules; RNA Interference; Renal Replacement Therapy; Renal Tissue; Renal tubule structure; Reporting; Research; Resources; Risk Factors; Role; Scientist; Serine; Signal Transduction; Technology; Therapeutic; Threonine; Tissue Harvesting; Training; Universities; Wait Time; Washington; Work; career; career development; cost; design; diabetic; epigenome; epigenomics; equity, diversity, and inclusion; experience; global health; health determinants; health disparity; hypertensive; improved; in vivo Model; injury and repair; innovation; kidney repair; knockout animal; mouse model; multiple omics; novel; novel therapeutic intervention; novel therapeutics; organic acid; repaired; response; single nucleus RNA-sequencing; single-cell RNA sequencing; skills; targeted treatment; transcriptome; transcriptome sequencing; transcriptomics

Project Summary/Abstract - Shayna T. J. Bradford, Ph.D. Americans of African descent are more than four times as likely to reach end-stage renal disease than those of European descent (2021 USRDS report). Acute kidney injury along with diabetes and hypertension are top risk factors for developing end-stage renal disease. Acute kidney injury can be initiated via diabetic and/or hypertensive events causing nephron injury, among other causes. New nephrons cannot regenerate after injury. Following acute kidney injury, epithelial cells lining proximal tubules of the nephron can repopulate damaged tubules to promote repair. However, a portion of cells fail to repair (termed failed-repair proximal tubule cells) and express proinflammatory and profibrotic markers. Failed-repair proximal tubule cells are hypothesized to cause local inflammation and fibrosis which can promote the acute kidney injury to chronic kidney disease transition, which leads to end-stage renal disease. Using single nucleus RNA-seq we identified a Traf2 and Nck interacting kinase (Tnik) to be specifically expressed in failed-repair proximal tubule cells after acute kidney injury in mice. In this MOSAIC K99/R00 career development proposal, Dr. Shayna Bradford aims to define the role of Tnik in failed-repair proximal tubule cells using a novel mouse model with Tnik ablation specifically in renal tubules. Additionally, she aims to use start-of-the-art single cell multiomic technologies to define the role of failed- repair proximal tubule cells in the advanced acute kidney injury to chronic kidney disease transition in African Americans. Dr. Bradford’s career goal is to be at the forefront of unraveling the molecular mechanisms of renal health disparities in order to develop novel therapeutics to lessen gaps in renal health. Her career development plan consists of gaining expertise in single cell biology and computation, in vivo modeling of renal injury and regeneration, molecular determinants of health disparities, and in additional scientific training areas. She will also continue to build professional Diversity, Equity, and Inclusion skills in order to promote safe and inclusive training experiences in biomedical research. The K99 phase of the MOSAIC award will be carried out under the direction of Dr. Benjamin Humphreys, a distinguished physician-scientist in renal disease research and single cell biology at Washington University. The award will also be guided by an exceptional Faculty Advisory Committee with expertise in multiomics, mouse models of renal regeneration, and health disparities. Washington University is well known for excellence in research and has state-of-the art facilities and robust resources to carry out the proposed studies and career development plans.

项目摘要/摘要-Shayna T.J.Bradford博士 非洲裔美国人罹患终末期肾病的可能性是非裔美国人的四倍多 欧洲人后裔(2021年USRDS报告)。急性肾损伤以及糖尿病和高血压是最大的风险。 发生终末期肾病的因素。急性肾损伤可通过糖尿病和/或 高血压事件导致肾单位损伤，以及其他原因。新的肾单位在受伤后不能再生。 急性肾损伤后，肾单位近端小管上皮细胞可再生受损。 小管促进修复。然而，部分细胞无法修复(称为修复失败的近端小管细胞)。 并表达促炎症和促纤维化标志物。修复失败的近端小管细胞被假设为 引起局部炎症和纤维化，可促进急性肾损伤转化为慢性肾脏病 过渡，这会导致终末期肾病。利用单核RNA-seq，我们鉴定了一个Traf2和Nck 急性肾损伤后修复失败的近端小管细胞特异性表达相互作用蛋白 在老鼠身上。在这份镶嵌的K99/R00职业发展提案中，Shayna Bradford博士的目标是定义 TNIK在修复失败的近端小管细胞中的作用--使用一种新的小鼠模型 小管。此外，她的目标是使用最先进的单细胞多组学技术来定义失败的- 修复近曲小管细胞在非洲晚期急性肾损伤向慢性肾脏疾病过渡中的作用 美国人。布拉德福德博士的职业目标是走在解开肾脏分子机制的前沿 为了开发新的治疗方法以缩小肾脏健康方面的差距，我们将继续努力消除健康差距。她的事业发展 计划包括获得单细胞生物学和计算方面的专业知识，肾脏损伤的活体模型和 再生，健康差距的分子决定因素，以及其他科学培训领域。她会的 还继续培养专业多样性、公平性和包容性技能，以促进安全和包容 生物医学研究方面的培训经验。马赛克奖的K99阶段将在 本杰明·汉弗莱斯博士的指导，他是肾脏疾病研究领域的杰出内科科学家和单身人士 华盛顿大学的细胞生物学。该奖项还将由一位特殊的教师顾问指导 该委员会在多组学、小鼠肾脏再生模型和健康差异方面拥有专业知识。华盛顿 大学以卓越的研究而闻名，拥有最先进的设施和强大的资源来 执行拟议的学习和职业发展计划。