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Mechanisms of Successful vs. Failed Kidney Repair

Award Number: R01DK103740
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: 09/01/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Mechanisms of Successful vs. Failed Kidney Repair - ABSTRACT Outcomes after acute kidney injury (AKI) cover a wide spectrum ranging from full recovery to failed repair and transition to chronic kidney disease. Medicare patients aged 66 years and older who were hospitalized for AKI had a 35% cumulative probability of a recurrent AKI hospitalization within one year and 28% developed chronic kidney disease (CKD) in the year following hospitalization (the “AKI to CKD transition”). Work from our laboratory and others has demonstrated that proximal tubule repairs through injury-induced dedifferentiation of mature proximal tubule cells. A cardinal feature of proximal tubule dedifferentiation is increased proliferative capacity, but the mechanisms governing this process are incompletely understood. Moreover, in cases of severe or repetitive injury, proximal tubule epithelia become arrested in the G2/M phase of the cell cycle, leading to profibrotic cytokine secretion, tubulointerstitial fibrosis and CKD. The long term goal of this application is to define the molecular mechanisms of proximal tubule cell cycle progression and test whether this can be manipulated to promote successful repair. We have identified the specific and strong upregulation of the transcription factor forkhead box protein M1 (FoxM1) in injured proximal tubule after injury with subsequent downregulation by day 14. FoxM1 drives transcription of proliferation-related genes, and regulates both G1/S and G2/M phases of the cell cycle. We show that the epithelial growth factor receptor (EGFR) regulates FoxM1 expression both in vitro and in vivo, and knockdown of FoxM1 in primary renal proximal tubule epithelial cells (RPTECs) inhibits cell proliferation. EGFR activation in proximal tubule is also known to activate Yes-Associated Protein (Yap) and Tea Domain transcription factors (TEAD) which in turn regulates cell proliferation after AKI. Based on published and preliminary data, we propose that AKI leads to EGFR- dependent upregulation of FoxM1 via AKT and Yap/TEAD, causing pro-repair proximal tubule proliferation. We further hypothesize that failed repair and profibrotic G2/M arrest in proximal tubule can be prevented by inducible FoxM1 expression, driving a G2 transcriptional program, cell cycle progression and successful repair. In Aim 1 we examine the roles of EGFR, Hippo and FoxM1 signaling networks in proximal tubule epithelia. In Aim 2, we define the role of FoxM1 in successful repair after ischemia-reperfusion injury using a conditional deletion strategy. In Aim 3 we ask whether tubule-specific, transient expression of constitutively active FoxM1 (FoxM1∆N) can rescue pro-fibrotic G2/M cell cycle arrest and failed repair.


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 = $696,875 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	1/22/2026	COMPETING CONTINUATION	$695,859
2026	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	1/28/2026	NON-COMPETING CONTINUATION	$1,016
														Subtotal = $696,875

Issue Date FY: 2025 ( Subtotal = -$1,016 )
2025	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	9/11/2025	NON-COMPETING CONTINUATION	-$1,016
														Subtotal = -$1,016

Issue Date FY: 2023 ( Subtotal = $382,186 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	5/10/2023	NON-COMPETING CONTINUATION	$382,186
														Subtotal = $382,186

Issue Date FY: 2022 ( Subtotal = $382,186 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	4/27/2022	NON-COMPETING CONTINUATION	$382,186
														Subtotal = $382,186

Issue Date FY: 2021 ( Subtotal = $382,186 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	7	4/6/2021	NON-COMPETING CONTINUATION	$382,186
2021	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	2/19/2021	COMPETING CONTINUATION	$3,699
2021	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	2/19/2021	NON-COMPETING CONTINUATION	-$3,699
2021	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/11/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $382,186

Issue Date FY: 2020 ( Subtotal = $382,186 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	3/13/2020	COMPETING CONTINUATION	$382,186
														Subtotal = $382,186

Issue Date FY: 2019 ( Subtotal = $343,125 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/20/2019	NON-COMPETING CONTINUATION	$343,125
														Subtotal = $343,125

Issue Date FY: 2018 ( Subtotal = $343,125 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/16/2018	NON-COMPETING CONTINUATION	$343,125
														Subtotal = $343,125

Issue Date FY: 2017 ( Subtotal = $343,125 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/13/2017	NON-COMPETING CONTINUATION	$343,125
														Subtotal = $343,125

Issue Date FY: 2016 ( Subtotal = $343,125 )
2016	2016	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/22/2016	NON-COMPETING CONTINUATION	$343,125
														Subtotal = $343,125

Issue Date FY: 2015 ( Subtotal = $343,125 )
2015	2015	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/25/2015	NEW	$343,125
														Subtotal = $343,125

Grand Total All Awards = $3,940,228

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Mechanisms of Successful vs. Failed Kidney Repair

Award Number: R01DK103740

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: 09/01/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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