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SGK Regulation of Epithelial Sodium Transport

Award Number: R01DK056695
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: 08/15/2000
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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SGK Regulation of Epithelial Sodium Transport - PROJECT SUMMARY/ABSTRACT Regulated transport of Na+ and K+ in the kidney tubules is central to blood pressure regulation and fluid and electrolyte homeostasis. The mTORC2-SGK1-ENaC axis is a well-established component of this regulatory machinery, however, key mechanistic features remain poorly characterized, and in vivo data is limited. We have used in vivo and in vitro approaches to identify novel features of this signaling system, particularly its role in K+ homeostasis. Our recent data suggest that: 1) K+ acts through WNK kinases to activate mTORC2; 2) tubule cell mTORC2 is central to the rapid response to a K+ load in mice; 3) Structural features of mTORC2, elucidated using cryo-EM, play an essential role in mTORC2 activity and specificity. To explore these hypotheses, we will: Aim 1: Assess the temporal sequence of responses to K+ in mice with tubule-specific knockout of mTORC2. We have generated a rapidly inducible kidney tubule-specific Rictor KO (TRKO) mouse model. Preliminary data show that these mice fail to respond to KCl normally; differences between WT and KO mice manifest in <3h following KCl gavage, and are striking by 48 h of high K diet. To characterize these mice, we will determine: (A) Time course of response to acute KCl load. Mice will be treated with an oral K+ load and urinary and plasma parameters will be assessed. Kidneys will be harvested and assessed for tissue signaling parameters and ion transporter expression and modification. ENaC, ROMK, and BK channel activities will be measured using patch clamp. Cytoplasm from patched cells will be captured and mRNA subjected to RNA-seq to identify single-cell gene expression patterns. (B) Time course of gene deletion: Mice will be adapted to a high K+ diet prior to initiating gene deletion. Balance experiments will be performed on adrenal-intact and ADX + aldo mice at time points prior to and during emergence of phenotype. Patch clamp will be performed and cytoplasmic RNA harvested and analyzed as in (A). (C) Evaluate PKC role and identify novel targets. We will identify key PKC substrates using LC/MS, and functionally characterize them in vivo and in cultured cells. Aim 2: mTORC2 molecular signaling mechanisms and specificity: structural features and effects of WNK kinases. We will establish the cellular and molecular features that underlie mTORC2 regulation of SGK1 using cultured cells and cryo-EM. (A) Investigate WNK1 and WNK4 as scaffolds that promote mTORC2-dependent phosphorylation of SGK1 in a K+-dependent fashion. We will examine effects of WNK kinases on physical interactions and phosphorylation of SGK1, and functional effects on ENaC and ROMK in cultured mpkCCD and HEK-293 cells. (B) Cryo-EM structural analysis of mTORC2 core complex, and with SGK1 and WNK1. mTORC2 core components will be subjected to cryo-EM in the presence and absence of SGK1 and WNK kinases. Aim 3: Assess the roles of WNK1 and WNK4 and functional interactions with mTORC2 in vivo using inducible KO models. WNK1 and WNK4 inducible KO mice will be characterized similarly to TRKO in aim 1A; Na+ and K+ handling, and biochemical features will be investigated.


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 = $446,418 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	3/4/2025	NON-COMPETING CONTINUATION	$446,418
														Subtotal = $446,418

Issue Date FY: 2024 ( Subtotal = $475,634 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	21	5/17/2024	NON-COMPETING CONTINUATION	$29,728
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	1/25/2024	NON-COMPETING CONTINUATION	$445,906
														Subtotal = $475,634

Issue Date FY: 2023 ( Subtotal = $494,029 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	2/8/2023	NON-COMPETING CONTINUATION	$494,029
2023	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	19	5/12/2023	COMPETING CONTINUATION	-$5,127
2023	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	18	5/12/2023	NON-COMPETING CONTINUATION	$5,127
														Subtotal = $494,029

Issue Date FY: 2022 ( Subtotal = $492,607 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	19	4/29/2022	COMPETING CONTINUATION	$0
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	19	2/2/2022	COMPETING CONTINUATION	$492,607
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	19	6/3/2022	COMPETING CONTINUATION	$5,127
2022	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	18	6/3/2022	NON-COMPETING CONTINUATION	-$5,127
2022	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	1/21/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $492,607

Issue Date FY: 2021 ( Subtotal = $363,375 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	3/30/2021	NON-COMPETING CONTINUATION	$363,375
														Subtotal = $363,375

Issue Date FY: 2020 ( Subtotal = $362,812 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	3/24/2020	NON-COMPETING CONTINUATION	$362,812
														Subtotal = $362,812

Issue Date FY: 2019 ( Subtotal = $360,844 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	16	3/21/2019	NON-COMPETING CONTINUATION	$360,844
2019	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	2/28/2019	COMPETING CONTINUATION	$0
														Subtotal = $360,844

Issue Date FY: 2018 ( Subtotal = $359,276 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	6/19/2018	COMPETING CONTINUATION	$360,000
2018	2015	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	1/4/2018	NON-COMPETING CONTINUATION	-$724
														Subtotal = $359,276

Issue Date FY: 2015 ( Subtotal = $336,038 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	8/17/2015	NON-COMPETING CONTINUATION	$336,038
														Subtotal = $336,038

Issue Date FY: 2014 ( Subtotal = $336,038 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	8/7/2014	NON-COMPETING CONTINUATION	$336,038
														Subtotal = $336,038

Issue Date FY: 2013 ( Subtotal = $324,277 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	8/21/2013	NON-COMPETING CONTINUATION	$324,277
														Subtotal = $324,277

Issue Date FY: 2012 ( Subtotal = $336,038 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	9/17/2012	NON-COMPETING CONTINUATION	$336,038
														Subtotal = $336,038

Issue Date FY: 2011 ( Subtotal = $336,038 )
2011	2011	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	9/20/2011	COMPETING CONTINUATION	$336,038
2011	2010	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	9/19/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $336,038

Issue Date FY: 2010 ( Subtotal = $298,375 )
2010	2010	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	1/26/2010	NON-COMPETING CONTINUATION	$298,375
2010	2009	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Trans-NIH Recovery Act Research Support	000	8	10/19/2009	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $298,375

Issue Date FY: 2009 ( Subtotal = $410,963 )
2009	2009	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	3/5/2009	NON-COMPETING CONTINUATION	$30,138
2009	2009	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	12/17/2008	NON-COMPETING CONTINUATION	$271,251
2009	2009	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Trans-NIH Recovery Act Research Support	002	8	9/29/2009	SUPPLEMENT FOR EXPANSION	$109,574
2009	2009	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Trans-NIH Recovery Act Research Support	003	8	10/15/2009	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $410,963

Issue Date FY: 2008 ( Subtotal = $300,902 )
2008	2008	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Kidney Diseases, Urology and Hematology Research	000	7	12/19/2007	NON-COMPETING CONTINUATION	$300,902
														Subtotal = $300,902

Issue Date FY: 2007 ( Subtotal = $306,047 )
2007	2007	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Kidney Diseases, Urology and Hematology Research	000	6	12/22/2006	NON-COMPETING CONTINUATION	$306,047
														Subtotal = $306,047

Issue Date FY: 2006 ( Subtotal = $312,626 )
2006	2006	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Kidney Diseases, Urology and Hematology Research	000	5	12/16/2005	COMPETING CONTINUATION	$312,626
														Subtotal = $312,626

Grand Total All Awards = $7,581,589

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SGK Regulation of Epithelial Sodium Transport

Award Number: R01DK056695

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: 08/15/2000

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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