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

项目概要/摘要- Shayna T. J. Bradford博士 非裔美国人患终末期肾病的可能性是非裔美国人的四倍多。 欧洲血统（2021年USRDS报告）。急性肾损伤沿着糖尿病和高血压是最高风险 发展为终末期肾病的因素。急性肾损伤可以通过糖尿病和/或糖尿病性疾病引发。 引起肾单位损伤的高血压事件，以及其他原因。损伤后新肾单位不能再生。 急性肾损伤后，肾单位近端小管的上皮细胞可以重新聚集在受损的细胞中， 小管促进修复。然而，一部分细胞无法修复（称为修复失败的近端小管细胞） 并表达促炎和促纤维化标记物。假设近端小管细胞修复失败， 引起局部炎症和纤维化，可促进急性肾损伤向慢性肾脏病发展 过渡，导致终末期肾病。使用单核RNA-seq，我们鉴定了Traf 2和Nck。 相互作用激酶（Tnik）在急性肾损伤后修复失败的近端小管细胞中特异性表达 对小鼠在这份MOSAIC K99/R 00职业发展提案中，Shayna Bradford博士旨在定义以下人员的角色 Tnik在近端小管细胞修复失败中的作用，使用一种新的小鼠模型，在肾脏中特异性进行Tnik消融 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作用， 在非洲晚期急性肾损伤向慢性肾脏疾病转变中修复近端小管细胞 美国人布拉德福德博士的职业目标是站在揭开肾脏疾病分子机制的最前沿。 为了开发新的治疗方法来缩小肾脏健康方面的差距，她的职业发展 计划包括获得单细胞生物学和计算方面的专业知识，肾损伤的体内建模， 此外，还将在再生、健康差距的分子决定因素以及其他科学培训领域开展工作。她将 我们还将继续培养专业的多样性、公平性和包容性技能，以促进安全和包容性 生物医学研究方面的培训经验。MOSAIC奖的K99阶段将在 Benjamin Humphreys博士的指导，他是肾脏疾病研究领域的杰出医生-科学家， 华盛顿大学的细胞生物学。该奖项还将由一个特殊的教师咨询指导 该委员会在多组学、肾再生小鼠模型和健康差异方面具有专长。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， 开展拟议的研究和职业发展计划。

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.