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A new paradigm of glomerular immune cell homing

Award Number: R01DK135290
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: 12/15/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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A new paradigm of glomerular immune cell homing - SUMMARY This study aims to investigate a radically new paradigm of glomerular immune cell homing and to uncover the underlying cell and molecular mechanisms and their role in physiological and renal inflammatory disease conditions including diabetic kidney disease (DKD) and lupus nephritis (LN). As an additional translational aim, these studies will inform the repurposing of current treatments for kidney disease and the development of new anti-inflammatory therapies. Circulating and kidney resident immune cells are known to preferentially home in and around the glomerulus compared to other vascular beds in both normal and inflammatory states, suggesting the presence of unique immunomodulatory mechanisms in the glomerular microcirculation that protect the kidney filter. However, the underlying cell and molecular mechanisms have been largely unknown. The focus of the proposed studies is a new function of the cells of the macula densa (MD) which are strategically positioned at the glomerular vascular entrance and traditionally known to regulate renal and glomerular hemodynamics. Our laboratory recently identified that MD cells have the highest rate of protein synthesis among all kidney cell types and they secrete a variety of paracrine-acting angiogenic, cell growth and patterning, and extracellular matrix signaling proteins. Preliminary work identified the high MD-enrichment of several pathways and genes in the inflammatory response and cellular infiltration by leukocytes (e.g., Cxcl12, Cxcl14, Ptgs2, Ptges, Anxa1, Ccn1, Mif) and observed the MD-centric glomerular density and migration of CD44+ and CD8+ T cells in inflammatory diseases including lupus nephritis. Our central hypothesis is that MD cells drive the preferential glomerular homing of immune cells by the release of paracrine-acting pro-inflammatory factors including chemokines and cytokines. This project will use comprehensive experimental approaches including new transgenic mice with conditional, inducible and optogenetic tools (MD-mTORgof/lof, MD-Ai27, MD-Ai39, CCN1-knockout (KO), CCN1- GFP mice), models of renal and systemic inflammation (NTS, STZ-DKD, NZM.2328 LN models), in vivo MPM imaging, MD transcriptome analysis, in vitro cell culture and proteomics, and pre-clinical therapeutic translation. The specific aims are to (1) Examine the global immunomodulatory role and mechanisms of MD cells under physiological and renal inflammatory disease conditions, (2) Elucidate the renal anti-inflammatory role of CCN1, and (3) Test the anti-inflammatory effects of SGLT2 inhibitors (SGLT2i). These newly identified MD mechanisms may be targeted and will inform the development of future anti-inflammatory therapeutic strategies.


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 = $474,972 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/19/2025	NON-COMPETING CONTINUATION	$474,972
														Subtotal = $474,972

Issue Date FY: 2025 ( Subtotal = $427,475 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/28/2024	NON-COMPETING CONTINUATION	$427,475
														Subtotal = $427,475

Issue Date FY: 2024 ( Subtotal = $455,974 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/2/2024	NON-COMPETING CONTINUATION	$28,499
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/2/2023	NON-COMPETING CONTINUATION	$427,475
														Subtotal = $455,974

Issue Date FY: 2023 ( Subtotal = $474,972 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/9/2022	NEW	$474,972
														Subtotal = $474,972

Grand Total All Awards = $1,833,393

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A new paradigm of glomerular immune cell homing

Award Number: R01DK135290

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: 12/15/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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