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The role of cyclin G1 and CDK5 in chronic kidney disease.

Award Number: R01DK121101
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: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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The role of cyclin G1 and CDK5 in chronic kidney disease. - Summary: Chronic kidney disease (CKD) affects 10% of the world’s population and is characterized by progressive fibrosis and loss of kidney function, leading to end stage renal disease. Effective therapies to prevent or curtail the advancement of fibrosis remains a major clinical challenge. Kidney proximal tubule cells (PTC) have the remarkable ability to respond to injury by entering an earlier developmental state, termed dedifferentiation, and dividing to replace lost cells. PTCs then redifferentiate to resume normal function. For over 100 years, however, it has been known that a subset of PTCs never fully redifferentiate, and these chronically injured PTCs are a main driver of fibrosis and CDK progression. Although recent studies have better characterized these cells, it remains unclear why these chronically injured PTCs can’t recover from injury, while neighboring cells can. In studies funded by this award, we made a breakthrough by discovering key players that regulate G2/M arrest, dedifferentiation, senescence and fibrosis in CKD, the atypical cyclin, cyclin G1, and its cyclin dependent kinase (CDK5). Using cyclin G1 or CDK5 knockout kidneys as tools, we experimentally dissected G2/M arrest from dedifferentiation and fibrosis. Surprisingly, we found that while G2/M arrest was more common in maladaptively repaired cells, its functional role in CKD progression was limited. Instead, we discovered cyclin G1/CDK5 induced a state of profibrotic dedifferentiation that led to senescence and CKD we termed ‘maladaptive dedifferentiation.’ In the current proposal, we aim to test the therapeutic potential of redifferentiating maladaptively dedifferentiated cells. In our preliminary data we found that the cyclin G1/CDK5 pathway regulates dynamin related protein 1 (Drp1) mediated mitochondrial fission. In vitro, we discovered that maladaptive dedifferentiation could be reversed by targeting the cyclin G1/CDK5 pathway or mitochondrial dysfunction via Drp1. If the PTCs progressed to senescence, however, they became much harder to redifferentiate. Importantly, these findings translated in vivo. In animal models we found selective deletion of Drp1 after recovery from AKI induced redifferentiation and prevented senescence. These data indicate that redifferentiation of maladaptively repaired PTC is possible. Based on these data, cyclin G1/CDK5-induced mitochondrial dysfunction promotes and extends maladaptive dedifferentiation in PTCs, preventing redifferentiation and promoting irreversible senescence. To test this hypothesis, we will: 1. Determine the ‘point- of-no-return’ for PTC redifferentiation. We will test if and when targeting the cyclin G1/CDK5 pathway promotes redifferentiation and prevents AKI-to-CKD transition using Cre promotors to target dedifferentiated or senescent cells specifically. 2. Determine if restoration of mitochondrial morphology is necessary for PTC redifferentiation. Using conditional knockout mice, specific inhibitors, and metabolic flux assays we will examine whether restoration of FAO promotes redifferentiation. This proposal represents a new direction for the field of CKD research by directly targeting the maladaptive dedifferentiated PTCs with redifferentiation therapies.


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: 2025 ( Subtotal = $590,289 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	5/28/2025	NON-COMPETING CONTINUATION	$590,289
2025	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	4/2/2025	COMPETING CONTINUATION	$244,765
2025	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/2/2025	NON-COMPETING CONTINUATION	-$244,765
														Subtotal = $590,289

Issue Date FY: 2024 ( Subtotal = $623,839 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	7/15/2024	COMPETING CONTINUATION	$623,839
2024	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $623,839

Issue Date FY: 2023 ( Subtotal = $382,500 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/14/2023	NON-COMPETING CONTINUATION	$382,500
														Subtotal = $382,500

Issue Date FY: 2022 ( Subtotal = $382,500 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/25/2022	NON-COMPETING CONTINUATION	$382,500
														Subtotal = $382,500

Issue Date FY: 2021 ( Subtotal = $382,500 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/12/2021	NON-COMPETING CONTINUATION	$382,500
														Subtotal = $382,500

Issue Date FY: 2020 ( Subtotal = $382,500 )
2020	2020	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/11/2020	NON-COMPETING CONTINUATION	$382,500
														Subtotal = $382,500

Issue Date FY: 2019 ( Subtotal = $382,500 )
2019	2019	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/4/2019	NEW	$382,500
														Subtotal = $382,500

Grand Total All Awards = $3,126,628

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The role of cyclin G1 and CDK5 in chronic kidney disease.

Award Number: R01DK121101

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: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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