Controlling renal oxidative stress in CKD via targeting FGF23 bioactivity

通过靶向 FGF23 生物活性控制 CKD 中的肾脏氧化应激

• 批准号: 10886978
• 负责人: Rafiou Agoro
• 金额: $ 24.9万
• 依托单位: JACKSON LABORATORY
• 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 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10886978
• 关键词: Active Learning; Acute; Adenine; Affect; American; Anemia; Antioxidants; Asthma; Automobile Driving; Binding; Binding Sites; Bioinformatics; Bone Diseases; Cells; Chromatin; Chromosomal Rearrangement; Chronic Kidney Failure; Communication; Data; Data Analyses; Development Plans; Diet; Disease Progression; Distal; Doctor of Philosophy; Drug Metabolic Detoxication; Educational workshop; Elements; Endocrine System Diseases; Environment; Epidemic; Faculty; Fellowship; Fibroblast Growth Factor Receptors; Fostering; France; Genes; Genetic Polymorphism; Genomics; Goals; Grant; Heme; Hormones; Human; Hypertension; Immunology; Impairment; In Vitro; Indiana; Individual; Inflammation; Inflammatory; Injections; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Leadership; Learning; Ligands; LoxP-flanked allele; MAP Kinase Gene; Mediating; Mentors; Minerals; Mitochondria; Modification; Molecular; Mus; Nitrogen; Occupations; Oxidative Stress; Oxygen; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Phase; Phenotype; Positioning Attribute; Postdoctoral Fellow; Prevention; Production; Proteins; Proximal Kidney Tubules; Public Health; Reactive Oxygen Species; Renal function; Research; Research Activity; Research Personnel; Response Elements; Role; Signal Transduction; Stress; Testing; Training; Training Activity; Transgenic Mice; Transgenic Organisms; Tuberculosis; Universities; Vision; Wild Type Mouse; Work; bioinformatics resource; career; career development; conditional knockout; disorder risk; fibroblast growth factor 23; genome-wide; genomic data; heme oxygenase-1; improved; insight; interest; iron metabolism; medical schools; meetings; mitochondrial dysfunction; mouse model; new technology; new therapeutic target; novel; overexpression; promoter; receptor; response; skills; stress management; therapeutic target; transcriptomics; translational study

Project Summary: Rafiou Agoro, PhD is a molecular and cellular biologist whose overarching career goal is to identify promising therapeutic targets relevant for the prevention/treatment of chronic kidney disease (CKD). The proposed research in this K99/R00 application aims to identify novel pathways involved in the control of renal oxidative stress with translational applicability on halting CKD progression and improving patient outcomes. Candidate: Dr. Agoro completed a PhD in Immunology at Orléans University (France) followed with a fellowship at NYU before joining Dr. White’s lab at Indiana University School of Medicine (IUSM) as a postdoctoral fellow. Dr. Agoro’s previous work identified iron metabolism and inflammatory mechanisms involved in tuberculosis, asthma, and CKD pathogeneses giving him the strong background knowledge required to conduct the proposed research. In addition, Dr. Agoro outlined a career development roadmap in building skills in bioinformatics during the K99 phase with a vision of leveraging novel technologies to understand the pathogenesis of CKD as an independent investigator. Dr. Agoro proposes four career goals during the K99/training phase: 1) To master the scATACseq analytic pipelines; 2) To generate conditional mouse models; 3) To successfully find a faculty position and 4) To develop leadership and professional skills in communication. Further Dr. Agoro will undergo training activities that include didactic and experiential learning to enable him to gain the necessary skills for genomic data analyses. Mentors/Environment: Dr. Agoro and his primary mentor, Dr. White, PhD, have assembled a strong team formed with a co-mentor, collaborators, advisor, and consultant to assist Dr. Agoro through the proposed training, research activities, and faculty job search. The proposed career development plan will utilize the intellectual and bioinformatics resources at IUSM. In addition, Dr. Agoro will attend national meetings, as well as seminars/courses and workshops locally. Research: CKD is an important public health epidemic affecting approximately 37 million Americans. CKD disease progression is associated with a graded increase in oxidative stress driving highly adverse complications. This proposal will decipher novel pathways involved in renal stress control via the following specific aims: Aim 1 will identify the mechanisms by which Klotho-dependent FGF23 signaling regulates HMOX1. In Aim 2, Dr. Agoro will test the role of Klotho and Hmox1 in CKD pathogenesis with a specific focus on renal oxidative stress, iron metabolism and mitochondria function. Summary: The proposed research will profile the genome-wide chromatin accessibility of renal proximal tubule in Klotho-transgenic vs WT mice and study the effects of Klotho-dependent FGF23 signaling on Nrf2 binding to ARE elements. Dr. Agoro will also determine the role of the FGF23-Klotho-Hmox1 axis on renal oxidative stress during CKD. In sum, this comprehensive plan will provide Dr. Agoro with the training needed to conduct independent research using genomic and transcriptomic approaches to improve CKD patient outcomes.

Rafiou Agoro博士是一位分子和细胞生物学家，其首要职业目标是 确定与预防/治疗慢性肾病（CKD）相关的有前景的治疗靶点。的 在K99/R 00申请中提出的研究旨在确定参与控制肾脏疾病的新途径。 氧化应激在阻止CKD进展和改善患者结局方面具有转化适用性。 候选人：Agoro博士在奥尔良大学（法国）完成了免疫学博士学位，随后获得了研究金 在加入印第安纳州大学医学院（IUSM）的白色博士实验室之前，他在纽约大学担任博士后研究员。 博士Agoro之前的工作确定了与结核病有关的铁代谢和炎症机制， 哮喘和CKD的发病机制，为他提供了进行拟议研究所需的强大背景知识。 research.此外，Agoro博士还概述了在生物信息学领域培养技能的职业发展路线图。 K99阶段的愿景是利用新技术来了解CKD的发病机制， 独立调查员Agoro博士在K99/培训阶段提出了四个职业目标：1）掌握 scATACseq分析管道; 2）生成条件小鼠模型; 3）成功找到一个教师 4）培养领导能力和沟通的专业技能。亚吾郎博士将接受 培训活动，包括教学和体验学习，使他能够获得必要的技能， 基因组数据分析。导师/环境：Agoro博士和他的主要导师白色博士， 我组建了一个强大的团队，由共同导师，合作者，顾问和顾问组成，以协助Agoro博士 通过拟议的培训，研究活动，和教师求职。拟议的职业发展 该计划将利用IUSM的知识和生物信息学资源。此外，Agoro博士将参加国家 会议，以及当地的研讨会/课程和讲习班。研究：CKD是一种重要的公共卫生 疫情影响约3700万美国人。CKD疾病进展与分级 氧化应激的增加导致高度不利的并发症。这项提案将破译新的途径 通过以下具体目标参与肾应激控制：目标1将确定 Klotho依赖性FGF 23信号传导调节HMOX 1。在目标2中，Agoro博士将测试Klotho和Hmox 1的作用 在CKD发病机制中，特别关注肾脏氧化应激、铁代谢和线粒体功能。 摘要：本研究将描述肾近曲小管全基因组染色质可及性 在Klotho转基因小鼠与WT小鼠中进行比较，并研究Klotho依赖性FGF 23信号传导对Nrf 2与 ARE元素。Agoro博士还将确定FGF 23-Klotho-Hmox 1轴在肾脏氧化应激中的作用 CKD期间。总而言之，这一全面的计划将为Agoro博士提供进行所需的培训， 使用基因组学和转录组学方法进行独立研究，以改善CKD患者的预后。