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，博士是一位分子和蜂窝生物学家，其总体职业目标是确定与预防/治疗慢性肾脏疾病（CKD）有关的有希望的治疗靶标。该K99/R00应用程序中的拟议研究旨在确定肾脏控制涉及的新途径氧化应激，并适用于停止CKD进展并改善患者预后的氧化应激。候选人：Agoro博士在法国奥尔莱恩斯大学（OrléansUniversity）（法国）获得了免疫学博士学位在纽约大学加入印第安纳大学医学院（IUSM）的怀特博士实验室之前，作为博士后研究员。 Agoro博士以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病原体为他提供了进行拟议的强大背景知识研究。此外，Agoro博士概述了在生物信息学中建立生物信息学技能的职业发展路线图 K99阶段具有利用新技术来理解CKD的发病机理的视野独立研究者。 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）生成条件鼠标模型； 3）成功找到教师位置和4）发展沟通领域和专业技能。进一步的Agoro博士将接受培训活动，包括教学和经验丰富的学习，使他能够获得必要的技能基因组数据分析。导师/环境：Agoro博士和他的主要精神，怀特博士博士组建了一个由联合主管，合作者，顾问和顾问组成的强大团队，以协助Agoro博士通过拟议的培训，研究活动和教师求职。拟议的职业发展计划将利用IUSM的智力和生物信息学资源。此外，Agoro博士将参加国家会议，以及本地的半手/课程和讲习班。研究：CKD是重要的公共卫生流行病影响了约3700万美国人。 CKD疾病进展与分级有关氧化应激的增加驱动高度不利并发症。该提议将破译新颖道路通过以下特定目的参与肾应力控制：AIM 1将确定其机制 Klotho依赖性FGF23信号传导调节HMOX1。在AIM 2中，Agoro博士将测试Klotho和Hmox1的作用在CKD发病机理中，特别关注肾脏氧化应激，铁代谢和线粒体功能。摘要：拟议的研究将介绍肾脏代理管的全基因组染色质可及性在Klotho-Transgenic与WT小鼠中是元素。 Agoro博士还将确定FGF23-KLOTHO-HMOX1轴对肾脏氧化物应激的作用在CKD期间。总而言之，该全面计划将为Agoro博士提供进行进行的培训使用基因组和转录组方法的独立研究来改善CKD患者结果。