Controlling renal oxidative stress in CKD via targeting FGF23 bioactivity

项目摘要：Rafiou Agoro博士是一名分子和细胞生物学家，他的主要职业目标是 确定与慢性肾脏疾病(CKD)的预防/治疗相关的有前景的治疗目标。这个 在K99/R00应用中提出的研究旨在确定参与肾脏控制的新途径 氧化应激在阻止CKD进展和改善患者预后方面的翻译适用性。 候选人：Agoro博士在法国Orléans大学获得免疫学博士学位，之后获得奖学金 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，他在纽约大学工作。 阿戈罗博士之前的工作确定了与结核病有关的铁代谢和炎症机制， 哮喘和慢性肾脏病的发病机制使他具备了进行建议的 研究。此外，Agoro博士概述了在生物信息学方面建立技能的职业发展路线图 K99阶段的愿景是利用新技术来理解CKD作为一种 独立调查员。阿戈罗博士在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)成功找到教员 4)培养领导力和专业沟通能力。进一步的阿戈罗医生将接受 培训活动，包括指导性和体验式学习，使他能够获得必要的技能 基因组数据分析。导师/环境：阿戈罗博士和他的主要导师怀特博士 组建了一个强大的团队，由合作导师、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 PLAN将利用IUSM的智力和生物信息学资源。此外，阿戈罗博士还将参加全国 会议，以及当地的研讨会/课程和讲习班。研究：慢性肾脏病是一种重要的公共卫生 这一流行病影响了大约3700万美国人。CKD疾病的进展与分级的 氧化应激增加会导致严重的不良并发症。这项提议将破译新的途径。 通过以下具体目标参与肾应激控制：目标1将确定 Klotho依赖的FGF23信号调节Hmox1。在目标2中，阿戈罗博士将测试Klotho和Hmox1的作用 在CKD的发病机制中，特别关注肾脏氧化应激、铁代谢和线粒体功能。 摘要：拟议的研究将描述全基因组范围内肾近端小管染色质的可及性。 研究Klotho依赖的FGF23信号对Nrf2结合的影响 都是元素。阿戈罗博士还将确定FGF23-Klotho-Hmox1轴在肾脏氧化应激中的作用 在CKD期间。总而言之，这项全面的计划将为阿戈罗博士提供所需的培训 使用基因组和转录组方法的独立研究，以改善CKD患者的预后。

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.