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REGULATORS OF CALCINEURIN PATHWAYS AS DIAGNOSTIC AND THERAPEUTIC TARGETS FOR NEPHROTIC SYNDROME

Award Number: R01DK134347
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: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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REGULATORS OF CALCINEURIN PATHWAYS AS DIAGNOSTIC AND THERAPEUTIC TARGETS FOR NEPHROTIC SYNDROME - Nephrotic syndrome and other glomerular diseases are major causes of chronic kidney diseases world-wide. The molecular mechanisms of NS are not completely known, and this major gap in knowledge is an impediment to treating patients with NS and developing new treatments. A more complete understanding of the mechanisms underlying NS is critical for identification of robust non-invasive diagnostic tools and precise effective treatment options. In preliminary data, we identified pathogenic variants in the genes regulator of calcineurin (CN) types 1- 3 (RCAN1-3) in patients with NS. We showed that cells expressing mutant RCAN1 displayed elevated CN activity and increased apoptosis. These phenotypes were rescued by pharmacological inhibition of CN. Our findings suggest that variants in RCAN genes are novel genetic causes of NS, and that modulators of CN signaling may represent targeted therapy for individuals with NS induced by RCAN mutations, the more common idiopathic NS and other glomerular diseases. Despite the fact, that unregulated CN activation is central to the pathogenesis of multiple glomerular disease processes and CN inhibitors (CNIs) are often used for treatment, the signaling pathways regulated by RCAN proteins specifically are not well understood. Further, only ~30-50% of patients with steroid resistant NS will achieve remission with CNI treatment and there are currently no biomarkers to predict therapy response despite major side effects of CNI including nephrotoxicity. The overarching hypothesis of this study is that genetic defects in RCAN genes cause CNI responsive NS by reducing podocyte viability due to aberrant cytoskeletal dynamics that can be ameliorated by targeting modulators of RCAN activity. We will test our hypothesis through the following aims: 1) Determine the effect of pathogenic variants in RCAN genes on CNI therapy response in patients with NS, 2) Determine the molecular mechanisms mediating the aberrant phenotypes caused by pathogenic RCAN variants in patient derived iPSC podocytes and iPSC-kidney organoids, and 3) Identify targeted therapies that can rescue the aberrant RCAN phenotypes in ex-vivo podocytes. Data generated from these studies will define the role of genetic defects in RCAN genes in disease pathogenesis and CNI therapy response in patients with NS. In addition, the study will reveal podocyte signaling mechanisms that are dysregulated due to defective RCAN genes and ultimately lead to identification of novel or repurposed therapeutic alternatives to CNI treatment.


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 = $615,845 )
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/12/2026	NON-COMPETING CONTINUATION	$615,845
														Subtotal = $615,845

Issue Date FY: 2025 ( Subtotal = $598,348 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/17/2024	NON-COMPETING CONTINUATION	$598,348
														Subtotal = $598,348

Issue Date FY: 2024 ( Subtotal = $658,609 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/19/2024	NON-COMPETING CONTINUATION	$617,445
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/3/2024	NON-COMPETING CONTINUATION	$41,164
														Subtotal = $658,609

Issue Date FY: 2023 ( Subtotal = $713,262 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/31/2023	NEW	$713,262
														Subtotal = $713,262

Grand Total All Awards = $2,586,064

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REGULATORS OF CALCINEURIN PATHWAYS AS DIAGNOSTIC AND THERAPEUTIC TARGETS FOR NEPHROTIC SYNDROME

Award Number: R01DK134347

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: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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