Abnormal STAT3 Signaling and Aberrant O-Glycosylation of IgA1 in IgA Nephropathy

NIH RePORTER · NIH · K01 · $152,704 · view on reporter.nih.gov ↗

Abstract

Project Summary/Abstract The purpose of this proposal for the K01 Administrative Supplemental Award from the NIDDK is to enhance the learning and research skills of the applicant in order to transition into an independent investigator. The justification portion of this proposal outlines the critical timeframes that the COVID-19 restrictions occurred under, and how this led to ceased production when manuscripts and grant preliminary data was being generated. The research portion of this proposal is focused on the mechanisms of autoantigen production in IgA nephropathy (IgAN), and how the applicant will finish critical experiments necessary for a successful R01- A1 submission. The goal of the applicant is to become an independent investigator, and as a current assistant professor this will require more training and time. This will be accomplished through collaboration with mentors who have extensive experience in molecular biology research, and execution of experiments listed in the research strategy. The university has exceptional core programs set up to help young investigators with finding and writing grants, obtaining proper collaborative expertise, research training programs, and lab management courses. IgAN is an autoimmune disease, which leads to decreased kidney function, with 40-50% of patients requiring dialysis and/or transplantation. In this autoimmune disease, B cells from the immune system produce IgA1 that has an aberrant glycosylation (termed Gd-IgA1) that causes the body to recognize IgA1 as a foreign antigen. The autoantigen, Gd-IgA1, is elevated in IgAN patients and forms the basis for immune-complex formation, which deposits in the kidney, leading to progressive kidney damage. The aims of this proposal are to identify mechanisms responsible for elevated Gd-IgA1 production in patient B cells after cytokine exposure. Identification of specific glycosylation enzymes that are differentially regulated and over activation signal transducer and activator of transcription 3 (STAT3) by cytokines in IgAN patient B cells has provided us with a strong starting point. We propose to investigate mechanisms responsible for altered signaling in IgAN patients, thereby providing a bases for future drug development to reduce autoantigen production.

Key facts

NIH application ID
10384158
Project number
3K01DK106341-05S1
Recipient
UNIVERSITY OF ALABAMA AT BIRMINGHAM
Principal Investigator
Colin Robert Reily
Activity code
K01
Funding institute
NIH
Fiscal year
2021
Award amount
$152,704
Award type
3
Project period
2015-08-01 → 2022-07-31