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Dichotomous roles of Shroom3 in Tubular cells and Podocytes in native and allograft kidneys

Award Number: R01DK122164
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary: Chronic kidney disease (CKD) is identified as decline in renal function estimated by glomerular filtration rate (eGFR) and/or signified by the presence of proteinuria. By histology in native and allograft kidneys, CKD is characterized by renal interstitial fibrosis, vascular intimal fibrosis and glomerulo- sclerosis, reflecting damage to different renal compartments. Genome-wide association studies (GWAS) have identified candidate susceptibility loci for CKD. The mechanistic basis of GWAS-variant associations with CKD are largely undescribed, hindering translation of GWAS information for the development of novel therapies for CKD. We previously showed that a CKD-associated SHROOM3 locus - Rs17319721, in the donor kidney increased SHROOM3 expression (by TCF7L2-dependent transcription) and promoted renal allograft fibrosis (IF/TA), through TGF-ß1 signaling. These data contrast with evidence of a protective role for Shroom3 in glomerular development. Consistently, opposing associations were seen between glomerular- and non- glomerular SHROOM3, and renal function in CKD biopsies. In allografts, homozygosity at Rs173198721 ie A/A, which associated with lower GFR, was associated with reduced albuminuria by 2-years post-transplant. GWAS data also showed that Rs17319721 was associated with reduced albuminuria but reduced eGFR. To study mechanism of these dichotomous effects, we used inducible Shroom3 knockdown mice and observed reduced renal fibrosis with tubular Shroom3 knockdown. In tubular cells, Rho kinase (ROCK) inhibitors or ROCK-binding (ASD2-) domain deletion in Shroom3 reduced profibrotic signaling. Conversely, glomerular-, but not tubular-Shroom3 knockdown, induced albuminuria with diffuse podocyte foot process effacement without podocyte loss. This phenotype is similar to human minimal change disease (MCD). In podocytes, we identified & confirmed the novel interaction of SHROOM3 with FYN (a Src kinase) via a critical Src homology-3 binding domain, distinct from its ASD2-domain. In vitro and in vivo, Shroom3-Fyn interaction was required for activation of Fyn kinase and downstream Nephrin phosphorylation and actin cytoskeleton in podocytes. This novel mechanism explains the protective effect of Shroom3 (& Rs17319721) on proteinuria in adults. We hypothesize that SHROOM3 has dichotomous roles in renal tubular cells and podocytes, that are mediated by distinct protein motifs. We will test our hypothesis by three aims. In aim-1, we will overeprexpress ASD2- domain deficient Shroom3 in vitro/in vivo to confirm ASD2-domain dependent profibrotic signaling by Shroom3. In aim-2, Fyn-binding mutant Shroom3 will be overexpressed to confirm podocyte injury and phenotype in vivo. Since impaired Fyn activation is associated with MCD, and Shroom3 knockdown inhibited Fyn, in aim-3, we will investigate the relevance of Shroom3-Fyn interaction to human MCD by comparative glomerular morphometry and genomics utilizing human data from the Nephrotic syndrome NEPTUNE consortium. This work is essential to developing domain-specific Shroom3 inhibitors for fibrosis in CKD and IF/TA.


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: 2023 ( Subtotal = $376,875 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/18/2023	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $376,875

Issue Date FY: 2022 ( Subtotal = $381,552 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	7/18/2022	NON-COMPETING CONTINUATION	$376,875
2022	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	11/5/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$239,286
2022	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	9/26/2022	NON-COMPETING CONTINUATION	$4,677
2022	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/5/2021	NON-COMPETING CONTINUATION	-$239,286
														Subtotal = $381,552

Issue Date FY: 2021 ( Subtotal = $376,875 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	6/25/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$376,875
2021	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/24/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $376,875

Issue Date FY: 2020 ( Subtotal = $381,375 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	7/16/2020	NON-COMPETING CONTINUATION	$381,375
2020	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/15/2020	NEW	$0
														Subtotal = $381,375

Issue Date FY: 2019 ( Subtotal = $381,375 )
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/10/2019	NEW	$381,375
														Subtotal = $381,375

Grand Total All Awards = $1,898,052

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Dichotomous roles of Shroom3 in Tubular cells and Podocytes in native and allograft kidneys

Award Number: R01DK122164

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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