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Molecular Basis of Pathogenicity of IgA1-containing Immune Complexes

Award Number: R01DK078244
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2007
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Molecular Basis of Pathogenicity of IgA1-containing Immune Complexes - Abstract IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Unfortunately, many patients progress to kidney failure. IgAN is defined by the characteristic IgA1 mesangial deposits. Based on our published data, we proposed a hypothesis that describes sequential steps in the pathogenesis of IgAN. This multi-hit process is recognized by other researchers in the field as a blueprint for the development of disease-specific biomarkers and treatments. In the past funding period, we showed that most IgAN patients produce pathogenic IgA1-containing immune complexes. We determined that these complexes consist of polymeric IgA1 with some hinge-region O-glycans deficient in galactose (Gd-IgA1) and devoid of sialic acid (asialo-Gd-IgA1). These IgA1 glycoforms are recognized by IgG autoantibodies, resulting in the formation of circulating immune complexes, some of which deposit in glomeruli. We have determined that IgG in glomerular immunodeposits of IgAN patients is specific for asialo-Gd-IgA1. Using our in vitro and in vivo models of IgAN, we demonstrated that i) large-molecular-mass Gd-IgA1-IgG immune complexes are pathogenic; ii) complement C3 is covalently attached to IgA1 and IgG in these complexes; iii) C3 is required for the biological activity of those complexes in vitro and in vivo; and iv) these IgG-Gd-IgA1-C3 complexes activate multiple signaling pathways in mesangial cells. Despite progress in the identification of genetic and biochemical factors involved in IgAN pathogenesis, there are still many gaps in our knowledge. To address these gaps, we will use biospecimens from IgAN patients of opposing clinical phenotypes, i.e., with progressive vs. non-progressive disease, to determine the factors that are associated with disease progression. Based on our pilot experiments, we hypothesize that IgA1 immune complexes of IgAN patients with progressive disease have greater biological activity than do the complexes of patients with non-progressive IgAN. We further hypothesize that variances in the composition of these complexes determine differences in biological activity. For the circulating IgA1 immune complexes from IgAN patients with progressive vs. non-progressive disease, we will determine their size and biological activity (to induce cellular proliferation, signaling, and cytokine production in mesangial cells; Aim 1). We will determine molecular O-glycophenotypes of IgA1 in the circulating immune complexes of IgAN patients with progressive vs. non-progressive disease (Aim 2) and determine the impact of C3 processing and the presence of complement-regulating proteins on the activity of IgA1 immune complexes (Aim 3). To accomplish these goals, we have assembled a multidisciplinary team that will leverage our access to well-characterized clinical samples and our innovative in vitro and in vivo models of IgAN. Relevance: The results from these studies will provide molecular-level details concerning factors that determine the pathogenic potential of IgA1 immune complexes in IgAN. This knowledge will guide the development of future therapies of IgAN and provide critical information concerning the stratification of patients for clinical trials.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	2/24/2025	COMPETING CONTINUATION	$1
2025	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	2/24/2025	NON-COMPETING CONTINUATION	-$1
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $643,133 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	3/29/2024	COMPETING CONTINUATION	$643,133
														Subtotal = $643,133

Issue Date FY: 2023 ( Subtotal = $401,493 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	3/29/2023	NON-COMPETING CONTINUATION	$401,493
														Subtotal = $401,493

Issue Date FY: 2022 ( Subtotal = $401,493 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	5/10/2022	NON-COMPETING CONTINUATION	$401,493
														Subtotal = $401,493

Issue Date FY: 2021 ( Subtotal = $401,493 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	4/1/2021	NON-COMPETING CONTINUATION	$401,493
														Subtotal = $401,493

Issue Date FY: 2020 ( Subtotal = $406,783 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	4/1/2020	NON-COMPETING CONTINUATION	$406,783
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	4/23/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $406,783

Issue Date FY: 2019 ( Subtotal = $408,329 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	4/8/2019	COMPETING CONTINUATION	$408,329
2019	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	3/18/2019	EXTENSION WITH OR WITHOUT FUNDS	$0
2019	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	9	8/6/2019	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $408,329

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/17/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $219,750 )
2016	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	8/9/2016	EXTENSION WITH OR WITHOUT FUNDS	$219,750
														Subtotal = $219,750

Issue Date FY: 2015 ( Subtotal = $219,750 )
2015	2015	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	7/16/2015	NON-COMPETING CONTINUATION	$219,750
														Subtotal = $219,750

Issue Date FY: 2014 ( Subtotal = $219,750 )
2014	2014	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	7/16/2014	NON-COMPETING CONTINUATION	$219,750
														Subtotal = $219,750

Issue Date FY: 2013 ( Subtotal = $219,750 )
2013	2013	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/13/2013	COMPETING CONTINUATION	$219,750
														Subtotal = $219,750

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2011	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/1/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $236,627 )
2011	2011	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/3/2011	NON-COMPETING CONTINUATION	$236,627
														Subtotal = $236,627

Issue Date FY: 2010 ( Subtotal = $246,188 )
2010	2010	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/26/2010	NON-COMPETING CONTINUATION	$246,188
														Subtotal = $246,188

Issue Date FY: 2009 ( Subtotal = $250,135 )
2009	2009	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/16/2009	SUPPLEMENT FOR EXPANSION	$1,460
2009	2009	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/27/2009	NON-COMPETING CONTINUATION	$248,675
														Subtotal = $250,135

Issue Date FY: 2008 ( Subtotal = $248,675 )
2008	2008	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Kidney Diseases, Urology and Hematology Research	000	2	6/6/2008	NON-COMPETING CONTINUATION	$248,675
														Subtotal = $248,675

Issue Date FY: 2007 ( Subtotal = $253,750 )
2007	2007	UNIVERSITY OF ALABAMA AT BIRMINGHAM	UAB STATION, CBB 990	BIRMINGHAM	AL	35294	JEFFERSON	USA	Kidney Diseases, Urology and Hematology Research	000	1	5/3/2007	NEW	$253,750
														Subtotal = $253,750

Grand Total All Awards = $4,777,099

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Molecular Basis of Pathogenicity of IgA1-containing Immune Complexes

Award Number: R01DK078244

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2007

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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