Thursday, December 26, 2024 12/26/2024

The Paracrine Regulation of Mast Cells During Biliary/Cholangiocyte Repair and Damage

Award Number: R01DK108959
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

Cholangiopathies, including primary sclerosing cholangitis (PSC) are cholestatic liver diseases that target cholangiocytes. No definitive treatments for PSC exist and curative measures are elusive, thus translational studies are critically needed. PSC is characterized by ductular reaction (DR) encompassing enhanced bile duct mass, biliary senescence, inflammation, peribiliary fibrosis and increased portal mast cell (MC) presence/activation. During liver damage, MCs migrate to the liver and reside near damaged/senescent bile ducts and inhibition of biliary-derived senescent associated secretory phenotypes (SASP) reduces PSC phenotypes in mice. The exact source of MC infiltration/activation or stabilization remains unclear. Melatonin exerts its effects via specific receptors, MT1 and MT2, which are expressed by cholangiocytes and upregulated in cholestasis but have differential effects on liver damage. Knockdown of MT1 decreases cholestatic liver injury, whereas knockdown of MT2 increases cholestatic liver injury. Anti-inflammatory and anti-oxidant properties of melatonin are well-known; however, melatonin can also inhibit HA signaling, suggesting a link between these two molecules that, to date, has remained elusive. One key element between melatonin signaling and MC- histamine (HA) is the alarmin and SASP, IL-33, which is the ligand of the ST2 receptor (expressed on MCs) and IL-33/ST2 are upregulated in cholestasis. Since melatonin modulates IL-33/ST2 signaling which regulates MC activation/stabilization, there is a natural link between these two. Preliminary data demonstrates that (i) IL-33/ST2 signaling increases in human PSC and Mdr2-/- mice that correlates with increased HA content; (ii) Mdr2-/- mice treated with an ST2 inhibitor have reduced DR, inflammation and IL-33 content; and (ii) melatonin therapy decreases MC activation and biliary IL-33 content. These data support our overall hypothesis that, during liver damage, increased systemic and hepatic IL-33 levels induce MC infiltration/activation driving PSC phenotypes, which can be ameliorated via modulation of melatonin/MT-1 signaling. SA1 Hypothesis: Hepatic IL-33/ST2 signaling drives MC infiltration/activation and PSC phenotypes. We will evaluate (i) the cellular source(s) of IL- 33 using in vivo models and in vitro systems; and (ii) effects of IL-33/ST2 modulation on MC migration/activation and PSC phenotypes. SA2 Hypothesis: MCs infiltration increases IL-33 during liver damage and manipulation of MC mediators decreases IL-33/ST2 signaling. We will determine if (i) manipulation of MC-HA signaling directly alters IL-33/ST2 signaling, using cultured systems and 3D human organoids; (ii) changes in MC-HA/HR signaling in vivo mediates IL-33/ST2 outcomes and (iii) if manipulation of MCs in vitro affects PSC phenotypes. SA3 Hypothesis: Exogenous melatonin or manipulation of melatonin signaling decreases liver damage by stabilization of MCs and downregulation of IL-33/ST2 and there is an autocrine regulation of biliary melatonin that may reduce MC activation and IL-33/ST2. We will measure (i) effects of melatonin therapy on PSC outcomes; (ii) autocrine effects of biliary melatonin on IL-33/ST2 and disease phenotypes.


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 = $0 )
2025	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	11/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $430,234 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	3/11/2024	NON-COMPETING CONTINUATION	$403,344
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	5/29/2024	NON-COMPETING CONTINUATION	$26,890
														Subtotal = $430,234

Issue Date FY: 2023 ( Subtotal = $445,371 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	2/8/2023	NON-COMPETING CONTINUATION	$445,371
														Subtotal = $445,371

Issue Date FY: 2022 ( Subtotal = $438,397 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	7/20/2022	COMPETING CONTINUATION	$390
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	4/15/2022	COMPETING CONTINUATION	$438,397
2022	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	7/20/2022	NON-COMPETING CONTINUATION	-$390
														Subtotal = $438,397

Issue Date FY: 2020 ( Subtotal = $252,991 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	3/18/2020	NON-COMPETING CONTINUATION	$252,991
														Subtotal = $252,991

Issue Date FY: 2019 ( Subtotal = $252,991 )
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	5	7/24/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$191,965
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	7/19/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$252,991
2019	2018	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	7/24/2019	NON-COMPETING CONTINUATION	-$191,965
2019	2018	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/19/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $252,991

Issue Date FY: 2018 ( Subtotal = $3,876 )
2018	2018	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	4	4/28/2018	NON-COMPETING CONTINUATION	$207,270
2018	2017	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	3	1/22/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$137,782
2018	2017	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/12/2018	NON-COMPETING CONTINUATION	-$170,588
2018	2017	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/1/2017	NON-COMPETING CONTINUATION	-$170,588
2018	2017	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	1/12/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$81,995
2018	2016	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	1/12/2018	NEW	-$81,995
														Subtotal = $3,876

Issue Date FY: 2017 ( Subtotal = $922,428 )
2017	2017	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	013	3	9/14/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$81,995
2017	2017	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	015	2	9/14/2017	NON-COMPETING CONTINUATION	$170,588
2017	2017	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	006	3	8/11/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$252,583
2017	2017	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	019	2	9/14/2017	NON-COMPETING CONTINUATION	$170,588
2017	2017	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	009	3	9/14/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$170,588
2017	2017	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/15/2017	NON-COMPETING CONTINUATION	$25,213
2017	2017	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	020	3	9/14/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$81,995
2017	2017	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	7/17/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$69,488
2017	2017	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	017	2	9/14/2017	NON-COMPETING CONTINUATION	$170,588
2017	2017	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	7/17/2017	NON-COMPETING CONTINUATION	-$81,535
2017	2017	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	012	2	9/14/2017	NON-COMPETING CONTINUATION	$170,588
2017	2017	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	2	8/11/2017	NON-COMPETING CONTINUATION	-$170,588
2017	2017	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	010	3	9/14/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$81,995
2017	2017	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	016	3	9/14/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$81,995
2017	2017	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	008	2	9/14/2017	NON-COMPETING CONTINUATION	$170,588
2017	2017	SCOTT & WHITE MEMORIAL HOSPITL	2401 S 31ST ST	TEMPLE	TX	76504	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/25/2017	NON-COMPETING CONTINUATION	$226,910
2017	2016	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	018	1	9/14/2017	NEW	$81,995
2017	2016	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	011	1	9/14/2017	NEW	$81,995
2017	2016	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	014	1	9/14/2017	NEW	$81,995
2017	2016	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	1	8/11/2017	NEW	-$81,995
2017	2016	SCOTT & WHITE MEMORIAL HOSPITAL	2401 S 31ST ST	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	007	1	9/14/2017	NEW	$81,995
														Subtotal = $922,428

Issue Date FY: 2016 ( Subtotal = $252,123 )
2016	2016	SCOTT & WHITE MEMORIAL HOSPITAL	2401 SOUTH 31ST STREET	TEMPLE	TX	76508	BELL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/10/2016	NEW	$252,123
														Subtotal = $252,123

Grand Total All Awards = $2,998,411

Top

All Categories

About

Search

Reports

Data Submission

Award Information

The Paracrine Regulation of Mast Cells During Biliary/Cholangiocyte Repair and Damage

Award Number: R01DK108959

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer