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The immunomodulatory role of NECs in kidney health and disease

Award Number: R01DK144444
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: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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The immunomodulatory role of NECs in kidney health and disease - This project will explore and identify novel molecular and cellular mechanisms in the pathogenesis of lupus nephritis (LN), the most severe organ complication of systemic lupus erythematosus (SLE). LN is the main cause of morbidity and mortality in SLE patients. The primary role of the local tissue microenvironment in determining the immune response in SLE rather than systemic mechanisms has been newly recognized. We recently discovered a novel, neuronally differentiated scattered endothelial cell (EC) subtype termed neuroendothelial cells (NEC) with powerful anti-inflammatory functions. NECs have a well-defined arteriovenous zonal localization exclusively in small resistance arterioles with the highest density evident in kidney and brain. High resolution scRNA seq and transcriptome analysis of brain and kidney NECs identified cytokine-like 1 (Cytl1) as the top NEC specific secreted factor along with adaptor proteins, and elements of the cytokine/complement pathway associated with SLE. Preliminary data using intravital multiphoton microscopy (MPM) imaging of the local kidney and brain microcirculation combined with NEC genetic manipulation in vivo revealed that NEC-derived Cytl1 is a highly potent and novel anti-inflammatory cytokine. Importantly, the kidney and brain centered NEC organ distribution corresponds to the most common and severe end organ complications of SLE (LN and neuropsychiatric lupus, NPSLE) and NEC functions are consistent with the importance of vascular/endothelial mechanisms in the local tissue microenvironment in LN pathophysiology. Our proposed studies will determine whether targeting or altering NEC functions has disease modifying effect and provide therapeutic benefit in LN. Our overall, long-term vision is that novel therapeutic approaches, fundamentally different from the existing immune cell targeting strategies, will emerge from targeting the microvascular endothelium to reduce local tissue inflammation which will help to cure this complex and devastating disease. Our overarching hypothesis is that NEC/Cytl1 maintains vascular integrity and immune balance in the local tissue microenvironment and that endothelial dysfunction and activation secondary to NEC loss of function and reduced tissue levels of Cytl1 are critically important in the development of and potential therapy for LN. This project will use a comprehensive experimental approach including mouse models of LN, LN patient iPSC-derived human kidney tissues, intravital kidney vascular imaging with serial MPM, immune cell fate tracking in the intact mouse/human iPSC-derived kidney in vivo, AAV-RNA/ drug treatments in whole animals, and human translational studies using classic immunofluorescence, RNA-scope, and spatial transcriptome analysis. The specific aims of this project are to (i) Characterize the anti-inflammatory mode of action of NEC-derived Cytl1 in the renal microcirculation under physiological conditions, (ii) Examine the pathogenic role of altered NEC-derived Cytl1 in LN, (iii) Test the therapeutic potential of Cytl1 treatment in LN. Accomplishing these aims will open the door to exploiting NEC signaling mechanisms in future therapies for LN and other inflammatory kidney diseases.


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 = $599,437 )
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	1	8/10/2026	NEW	$599,437
														Subtotal = $599,437

Grand Total All Awards = $599,437

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The immunomodulatory role of NECs in kidney health and disease

Award Number: R01DK144444

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: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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