Controlling renal oxidative stress in CKD via targeting FGF23 bioactivity

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.

Grant Number: 5R00DK129705-05
NIH Institute/Center: NIH
Principal Investigator: Rafiou Agoro