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ABIN1 dysfunction in Lupus Nephritis

Award Number: R01DK126777
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: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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ABIN1 dysfunction in Lupus Nephritis - Project Summary Lupus nephritis (LN) is a common and severe complication of systemic lupus erythematosus (SLE), and current therapies are toxic and frequently ineffective. LN is more prevalent and more likely to cause kidney failure in African American patients [1-3]. SLE has strong genetic components, but the relationship of genetic susceptibility to prognosis in African Americans is poorly understood. Previous studies showed variants of TNIP1 are associated with SLE and LN susceptibility [4-7]. We reported a strong association for the TNIP1 rs4958881 polymorphism with LN in African American patients from a large-scale SLE genotyping study [8]. Our preliminary data show an association of the rs4958881 variants with severity and progression of LN in African Americans. TNIP1 encodes the protein ABIN1 that functions as a physiological inhibitor of NF-κB, a prominent immune regulator [9, 10]. We reported previously that loss of the molecular function of ABIN1 in mice results in SLE-like autoimmunity and glomerulonephritis [8, 11, 12]. While there is evidence that ABIN1 regulation of NF-B plays a role in autoimmunity and development of LN, a number of critical gaps in knowledge remain. First, what molecular mechanisms mediate ABIN1- dependent enhanced risk of LN, and are they specific for different immune cell types? Second, does altered ABIN1 function induced by TNIP1 polymorphisms play a role in the racial disparity of LN? Third, do TNIP1 polymorphisms have different pathologic, molecular, and cellular effects in African Americans compared with White Americans? Three Specific Aims are proposed to address these significant questions. Aim 1: Compare the Association of theTNIP1 variant rs4958881 on LN in White and African Americans. Aim 2: Determine the effects of the TNIP1 variant rs4958881 on monocyte, neutrophils, and B cell activity in patients with LN. Aim 3. Determine the mechanisms by which loss of ABIN1 molecular function alters monocyte, neutrophil, and B cell function using ABIN1 transgenic mice. The animal experiments will be interpreted in conjunction with similar experiments in Aim 2 using the same cells isolated from blood of LN patients with the TNIP1 rs4958881 risk variant. This is a Multi-PI proposal with a Cell and Molecular Biologist/Biochemist (Dr. David W. Powell) and a Clinical Nephrologist/Scientist (Dr. Dawn J. Caster). These investigators have published many of the reports pertaining to TINIP1/ABIN1 function in LN via genetic and animal studies and are now poised with recent preliminary findings to evaluate causative roles for a TNIP1 polymorphism in severity and progression and specific cellular and molecular events in human LN. The translational and population- targeted nature of these studies will provide impactful insights that will lead to precision diagnostics and therapeutics for high-risk African American LN patients.


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: 2024 ( Subtotal = $560,637 )
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/26/2024	NON-COMPETING CONTINUATION	$560,637
														Subtotal = $560,637

Issue Date FY: 2023 ( Subtotal = $583,996 )
2023	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/21/2023	NON-COMPETING CONTINUATION	$583,996
														Subtotal = $583,996

Issue Date FY: 2022 ( Subtotal = $583,996 )
2022	2022	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	8/2/2022	NON-COMPETING CONTINUATION	$583,996
2022	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/29/2022	NEW	$0
														Subtotal = $583,996

Issue Date FY: 2021 ( Subtotal = $596,388 )
2021	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/2/2021	NEW	$596,388
														Subtotal = $596,388

Grand Total All Awards = $2,325,017

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ABIN1 dysfunction in Lupus Nephritis

Award Number: R01DK126777

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: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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