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

基本信息

批准号：
10449584
负责人：
Rafiou Agoro
金额：
$ 9万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449584
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 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 MAP Kinase Gene Mediating Mentors Minerals Mitochondria Modification Molecular Mus Nitrogen Occupations Oxidative Stress Oxygen Pathogenesis Pathway interactions Patient-Focused Outcomes Phase Phenotype Play 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 Sum Testing Training Training Activity Transgenic Organisms Tuberculosis Universities Vision Wild Type Mouse Work base 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

项目摘要

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.

项目摘要：Rafiou Agoro 博士是一位分子和细胞生物学家，其总体职业目标是确定与预防/治疗慢性肾脏病（CKD）相关的有前景的治疗靶点。 K99/R00 申请中提出的研究旨在确定参与控制肾功能的新途径氧化应激对于阻止 CKD 进展和改善患者预后具有转化适用性。候选人：Agoro 博士在奥尔良大学（法国）获得免疫学博士学位，随后获得奖学金在加入怀特博士在印第安纳大学医学院 (IUSM) 的实验室担任博士后研究员之前，他在纽约大学就读。 Agoro 博士之前的工作确定了结核病中涉及的铁代谢和炎症机制，哮喘和 CKD 发病机制为他提供了进行拟议研究所需的强大背景知识此外，Agoro 博士概述了在生物信息学期间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 的发病机制独立研究者 Agoro 博士提出了 K99/培训阶段的四个职业目标： 1) 掌握 scATACseq 分析流程；2) 生成条件小鼠模型；3) 成功找到教师； 4) 为了培养领导力和沟通方面的专业技能，Agoro 博士将接受进一步的培训。培训活动包括教学和体验式学习，使他能够获得必要的技能基因组数据分析：Agoro 博士和他的主要导师 White 博士。组建了一个由共同导师、合作者、顾问和顾问组成的强大团队来协助 Agoro 博士通过拟议的培训、研究活动和教师求职。计划将利用 IUSM 的知识和生物信息学资源。此外，Agoro 博士将参加全国会议。会议，以及当地的研讨会/课程和讲习班研究：慢性肾病是一种重要的公共卫生问题。影响约 3700 万美国人的流行病与分级相关。氧化应激的增加会导致严重不良的并发症。该提案将破译新的途径。通过以下具体目标参与肾脏应激控制：目标 1 将确定以下机制： Klotho 依赖性 FGF23 信号传导调节 HMOX1 在目标 2 中，Agoro 博士将测试 Klotho 和 Hmox1 的作用。研究 CKD 发病机制，特别关注肾脏氧化应激、铁代谢和线粒体功能。摘要：拟议的研究将分析肾近曲小管的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 FGF23 信号传导对 Nrf2 结合的影响 Agoro 博士还将确定 FGF23-Klotho-Hmox1 轴对肾脏氧化应激的作用。总之，这个全面的计划将为 Agoro 博士提供进行 CKD 所需的培训。使用基因组和转录组学方法来改善 CKD 患者预后的独立研究。