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HuR/HIF – SIRT1 Signaling Axis in Liver Transplant Rejuvenation

Award Number: R01DK062357
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: 04/01/2003
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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HuR/HIF – SIRT1 Signaling Axis in Liver Transplant Rejuvenation - ABSTRACT Orthotopic liver transplantation (OLT) is the gold standard of care in patients with end-stage liver disease and those with tumors of hepatic origin. However, the scarcity of donor organs prompted the use of extended criteria “marginal” livers, which are particularly susceptible to ischemia-reperfusion injury (IRI), which predispose to acute/chronic rejection, and may require re-transplantation. We have introduced the concept of organ “rejuvenation”, i.e., conversion of the donor liver from the state of IRI-hypersensitivity to the homeostatic state of IRI-resistance. We have also proposed that SIRT1 deacetylase serves as a rheostat linking IR-stress with liver rejuvenation in both, mouse and human OLT. We have recently identified new regulators of hepatic resistance against warm vs. cold ischemia stress responses, i.e., Human Antigen R (HuR) and Hypoxia-Inducible Factor (HIF-1α). We have also discovered Ikaros (IKZF1), acts as a macrophage activation marker and exacerbates liver IRI. Importantly, we also found that preserved hepatocellular function/improved clinical outcomes in human OLT patients were associated with increased HuR/HIF-1α but depressed Ikaros levels in the liver biopsy samples. We hypothesize that crosstalk between hepatocyte HuR / HIF-1α and macrophage Ikaros provides a new means to regulate the adaptation of donor livers to IR-stress and reperfusion-mediated hepatic damage. Specific Aim 1: Determine mechanisms of hepatocyte HuR / HIF-1α crosstalk with SIRT1 in IRI-OLT. Hypothesis: Hepatocyte SIRT1 activation, controlled by distinct hypoxia/reoxygenation (H/R) requirements for HuR (warm H/R) vs. HIF-1α (cold H/R), provide new means to regulate adaptation of donor livers to IR-stress. 1.1: SIRT1 function is dependent on HuR signaling for anti-inflammatory responses in oxidative stress. 1.2: HuR/HIF-1α signaling in a mouse model of hepatic ischemia is temperature stress-dependent. 1.3: HIF-1α controls cold-induced IRI-OLT. 1.4: HuR controls warm-induced IRI-OLT. Specific Aim 2: Delineate mechanisms of macrophage Ikaros crosstalk with SIRT1 in IRI-OLT. Hypothesis: Macrophage Ikaros signaling exacerbates IRI-OLT by repressing SIRT1 transcription and M2 macrophage polarization. 2.1: Ikaros-SIRT1 myeloid axis influences hepatic HuR/HIF1α hypoxia sensing circuit in IRI-OLT. 2.2: Macrophage Ikaros signaling depends on SIRT1 transcription for M2 polarization. Specific Aim 3: Define mechanism of human liver rejuvenation under hypothermic machine preservation. Hypothesis: Manipulation of HIF-1α / SIRT1 axis during ex-vivo HMP improves hepatocellular function to rejuvenate human livers declined for transplantation due to preexisting poor quality. 3.1: Pharmacological stabilizer of HIF-1α protein synergizes with SIRT1 to improve human liver function. 3.2: Preconditioning with PHD-inhibitor, which activates/stabilizes HIF-1α, synergizes with enhanced SIRT1 signaling to ameliorate inflammation, promote cytoprotection, and rejuvenate human livers. These experiments are of high relevance to refine donor liver donation (DBD and DCD) as well as to improve quality/size of the current organ supply.


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 = $461,163 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	4/24/2025	NON-COMPETING CONTINUATION	$461,163
														Subtotal = $461,163

Issue Date FY: 2024 ( Subtotal = $442,717 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	5/9/2024	NON-COMPETING CONTINUATION	$442,717
														Subtotal = $442,717

Issue Date FY: 2023 ( Subtotal = $461,163 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	3/6/2023	NON-COMPETING CONTINUATION	$461,163
														Subtotal = $461,163

Issue Date FY: 2022 ( Subtotal = $461,163 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	3/25/2022	NON-COMPETING CONTINUATION	$461,163
														Subtotal = $461,163

Issue Date FY: 2021 ( Subtotal = $461,163 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	16	4/22/2021	COMPETING CONTINUATION	$0
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	16	3/17/2021	COMPETING CONTINUATION	$461,163
2021	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	15	9/25/2021	NON-COMPETING CONTINUATION	$0
2021	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	3/9/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $461,163

Issue Date FY: 2020 ( Subtotal = $426,948 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	2/11/2020	NON-COMPETING CONTINUATION	$426,948
														Subtotal = $426,948

Issue Date FY: 2019 ( Subtotal = $426,948 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	2/14/2019	NON-COMPETING CONTINUATION	$426,948
														Subtotal = $426,948

Issue Date FY: 2018 ( Subtotal = $426,948 )
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	4/23/2018	NON-COMPETING CONTINUATION	$42,695
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	2/22/2018	NON-COMPETING CONTINUATION	$384,253
														Subtotal = $426,948

Issue Date FY: 2017 ( Subtotal = $426,948 )
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	12	6/14/2017	NON-COMPETING CONTINUATION	$42,695
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	2/13/2017	NON-COMPETING CONTINUATION	$384,253
														Subtotal = $426,948

Issue Date FY: 2016 ( Subtotal = $426,948 )
2016	2016	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	3/1/2016	COMPETING CONTINUATION	$426,948
														Subtotal = $426,948

Issue Date FY: 2013 ( Subtotal = $316,795 )
2013	2013	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	3/4/2013	NON-COMPETING CONTINUATION	$295,457
2013	2013	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	5/20/2013	NON-COMPETING CONTINUATION	$21,338
														Subtotal = $316,795

Issue Date FY: 2012 ( Subtotal = $328,285 )
2012	2012	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	2/21/2012	NON-COMPETING CONTINUATION	$328,285
														Subtotal = $328,285

Issue Date FY: 2011 ( Subtotal = $328,285 )
2011	2011	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	5/26/2011	NON-COMPETING CONTINUATION	$29,844
2011	2011	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	3/3/2011	NON-COMPETING CONTINUATION	$298,441
														Subtotal = $328,285

Issue Date FY: 2010 ( Subtotal = $365,904 )
2010	2010	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	2/26/2010	NON-COMPETING CONTINUATION	$365,904
														Subtotal = $365,904

Issue Date FY: 2009 ( Subtotal = $985,600 )
2009	2009	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Trans-NIH Recovery Act Research Support	002	6	9/24/2009	SUPPLEMENT FOR EXPANSION	$616,000
2009	2009	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	3/20/2009	COMPETING CONTINUATION	$34,650
2009	2009	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	2/25/2009	COMPETING CONTINUATION	$334,950
														Subtotal = $985,600

Issue Date FY: 2007 ( Subtotal = $318,115 )
2007	2007	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Digestive Diseases and Nutrition Research	000	5	2/2/2007	NON-COMPETING CONTINUATION	$318,115
														Subtotal = $318,115

Issue Date FY: 2006 ( Subtotal = $327,616 )
2006	2006	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Digestive Diseases and Nutrition Research	000	4	2/7/2006	NON-COMPETING CONTINUATION	$327,616
														Subtotal = $327,616

Issue Date FY: 2005 ( Subtotal = $335,500 )
2005	2005	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Digestive Diseases and Nutrition Research	000	3	1/20/2005	NON-COMPETING CONTINUATION	$335,500
														Subtotal = $335,500

Issue Date FY: 2004 ( Subtotal = $335,500 )
2004	2004	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Digestive Diseases and Nutrition Research	000	2	1/26/2004	NON-COMPETING CONTINUATION	$335,500
														Subtotal = $335,500

Issue Date FY: 2003 ( Subtotal = $335,500 )
2003	2003	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Digestive Diseases and Nutrition Research	000	1		NEW	$335,500
														Subtotal = $335,500

Grand Total All Awards = $8,399,209

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HuR/HIF – SIRT1 Signaling Axis in Liver Transplant Rejuvenation

Award Number: R01DK062357

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: 04/01/2003

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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