The purpose of this proposal for the K01 Career Development Award from the NIDDK is to enhance the learning and research skills of the applicant in order to transition into an independent investigator. The career development aspect of this award is facilitated by his mentoring team, relevant courses, journal clubs, seminars, university centers, and cores dedicated to enhancing collaboration between clinicians and researchers. The research portion of this proposal is focused on the autoimmune disease IgA nephropathy (IgAN), which causes progressive kidney damage, and the mechanisms of autoantigen production. Identification of mechanisms involved in autoantigen production will allow for disease-specific therapies to be developed, which is absent in current therapeutic modalities. This has a huge cost burden on IgAN patients, both in terms of money and quality of life. The long-term goal of the applicant is to become an independent investigator, and as a current postdoc this will require more training and experience. This will be accomplished through collaboration with mentors who have extensive experience in molecular biology research, and specifically IgAN and kidney related diseases. 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. 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 bases for future drug development to reduce autoantigen production.

Public Health Relevance

IgA nephropathy (IgAN) is an autoimmune disease, where an individual's immune system attacks the kidney, causing slow kidney damage over time. The purpose of this study is to analyze the immune cells in IgAN patients, to ascertain why they cause damage, and thus provide a mechanism for future therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK106341-02
Application #
9116131
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK-D)
Program Officer
Rankin, Tracy L
Project Start
2015-08-01
Project End
2020-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2016
Total Cost
$152,704
Indirect Cost
$11,311
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Kiryluk, Krzysztof; Li, Yifu; Moldoveanu, Zina et al. (2017) GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. PLoS Genet 13:e1006609
Yamada, Koshi; Huang, Zhi-Qiang; Raska, Milan et al. (2017) Inhibition of STAT3 Signaling Reduces IgA1 Autoantigen Production in IgA Nephropathy. Kidney Int Rep 2:1194-1207
Maixnerova, Dita; Reily, Colin; Bian, Qi et al. (2016) Markers for the progression of IgA nephropathy. J Nephrol 29:535-41
Neprasova, Michaela; Maixnerova, Dita; Novak, Jan et al. (2016) Toward Noninvasive Diagnosis of IgA Nephropathy: A Pilot Urinary Metabolomic and Proteomic Study. Dis Markers 2016:3650909
Knoppova, Barbora; Reily, Colin; Maillard, Nicolas et al. (2016) The Origin and Activities of IgA1-Containing Immune Complexes in IgA Nephropathy. Front Immunol 7:117
Huang, Zhi Qiang; Raska, Milan; Stewart, Tyler J et al. (2016) Somatic Mutations Modulate Autoantibodies against Galactose-Deficient IgA1 in IgA Nephropathy. J Am Soc Nephrol 27:3278-3284