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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：
10597238
负责人：
Rafiou Agoro
金额：
$ 8.77万
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/10597238
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

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.

项目概述：Rafiou Agoro博士是一名分子和细胞生物学家，他的首要职业目标是