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Identifying autoimmune associated genes in patrolling monocytes that promote lupus nephritis

Award Number: R21AI178562
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Identifying autoimmune associated genes in patrolling monocytes that promote lupus nephritis - PROJECT SUMMARY Lupus nephritis (LN) is seen in ~50% of individuals with the chronic autoimmune disease systemic lupus erythematosus and is a serious cause of morbidity in this disease, with ~10% of SLE cases leading to end stage renal disease within 5 years of diagnosis. LN occurs disproportionately in women of non-European ancestry, including African-Americans, Hispanics and Asians, and despite many years of study, there are few targeted treatments. The recent approval of the first two specific LN therapeutics, belimumab and voclosporin targeting adaptive immune cells (T and B cells), was an important milestone. However, these therapeutics only have ~40% efficacy. Thus, a major challenge in the field is to identify therapies that treat or prevent LN in all patients. There is growing evidence that innate immune cells also contribute to LN. In particular, non-classical, patrolling monocytes have recently been implicated in glomerulonephritis, suggesting that a novel innate immune mechanism through recruitment of patrolling monocytes to the kidney contributes to LN, and that interfering with accumulation of patrolling monocytes early in disease could be therapeutically efficacious. There are no existing therapies that specifically target patrolling monocyte accumulation in the kidney, or other organs, thus, a better understanding of the genes and mechanisms that drive this process holds promise for identifying new therapeutic targets for LN and is the focus of this proposal. Informed by human lupus genetic risk loci, we will define key genes involved in patrolling monocyte accumulation in the kidney in LN. Though many genetic risk variants have been identified as associated with increased risk for SLE, the function of most genes regulated by these variants have not been systematically assessed in innate immune cells such as monocytes. We hypothesize that genes associated with GWAS risk variants may serve as a rich source of regulators of patrolling monocyte accumulation in glomerular capillaries and therefore of LN. To understand how genetic risk loci contribute to patrolling monocyte accumulation in LN, we will use an in vivo CRISPR screen using the TLR7.1 mouse model of lupus- like disease with validation in additional mouse lupus models. Upon completion, we will illuminate genes and pathways that may be targeted by novel therapeutic interventions, which could be used prior to the onset of kidney nephritis. Additionally, risk haplotypes correlated with identified genes could help predict the efficacy of such therapeutic approaches as well as risk for LN.


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: 2026 ( Subtotal = $0 )
2026	2024	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	2	5/5/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $216,625 )
2024	2024	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	2	5/30/2024	NON-COMPETING CONTINUATION	$216,625
														Subtotal = $216,625

Issue Date FY: 2023 ( Subtotal = $259,950 )
2023	2023	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	1	6/21/2023	NEW	$259,950
														Subtotal = $259,950

Grand Total All Awards = $476,575

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Identifying autoimmune associated genes in patrolling monocytes that promote lupus nephritis

Award Number: R21AI178562

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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