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Growth Regulation of the Intrahepatic Biliary Tree

Award Number: R01DK054811
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: 09/01/2000
PERIOD OF PERFORMANCE END DATE: 11/30/2022

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Growth Regulation of the Intrahepatic Biliary Tree - PROJECT SUMMARY/ABSTRACT The biliary epithelium is a complex network of interconnected ducts that increase in diameter from small to large bile ducts. It has been proposed that small cholangiocytes contain a population of biliary committed progenitors, showing expression of various biliary progenitor markers, and incorporate into neo-bile ducts at the sites of injury. When large cholangiocytes are damaged, small, Ca2+-dependent cholangiocytes are activated, acquiring phenotypic and functional features of large cholangiocytes and resulting in the repopulation of the injured large bile ducts. Cholestatic liver diseases (CLDs) such as Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC), are chronic diseases that slowly damage the intrahepatic and extrahepatic bile ducts including both small and large bile ducts. During CLDs and other human diseases, extracellular vesicles (EVs) are released by almost all cells (including hepatobiliary progenitors and cholangiocytes) in resting and activated conditions. Their mechanisms of actions are being elucidated and their potential role in health and disease is drawing increasing attention. However, the specific roles of non-coding RNAs (ncRNAs) in cholangiocytes derived EVs during hepatobiliary tissue repair (especially their characteristics during cholestatic liver injury) still need to be addressed. Based on our compelling data, we propose the central hypothesis that ncRNAs in small cholangiocytes derived extracellular vesicles contribute to the recovery of cholestatic liver injury through induction of growth and anti- senescence/anti-inflammation of hepatobiliary tissues and cells. In this application, we propose the systematic evaluation of stemness dependent ncRNAs as markers in small cholangiocytes derived EVs with the therapeutic potentials for cholestatic liver injury. We will address our central hypothesis by focusing on the following specific aims: 1) To define the biliary extracellular vesicle associated ncRNAs signaling involved in anti-inflammation process in hepatobiliary cells. In this study, we will characterize the interactions between miR-125b/let-7 and uc.338/uc.189 family members; define the role of anti-LPS ncRNA signaling in small cholangiocytes derived extracellular vesicles through flow cytometry and real-time PCR analysis. 2) To determine the effects of SMCC-EV associated ncRNAs on accelerating the morphologic and functional recovery of cholestatic liver injury in CLD mice induced in vivo by BDL or in the genetic mouse model of PSC and PBC, Mdr2-/- and dnTGFbRII, respectively. Therapeutic effects of EVs derived from SMCCs with miRNAs or inhibition of T-UCRs on hepatobiliary cell proliferation and inflammation, senescence and fibrosis will be evaluated. The results of the proposed studies may lead to new therapeutic strategies for human cholestatic liver diseases. Meanwhile, the acquired fundamental new knowledge about regulation of growth and tissue repair during cholestatic liver damage by hepatobiliary progenitors derived EVs is expected to advance the general field of anti-inflammatory biology and emerging therapeutic opportunities.


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: 2023 ( Subtotal = -$2,880 )
2023	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	6/6/2023	NON-COMPETING CONTINUATION	-$2,880
														Subtotal = -$2,880

Issue Date FY: 2021 ( Subtotal = $315,486 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	11/18/2020	NON-COMPETING CONTINUATION	$283,936
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	17	2/2/2021	NON-COMPETING CONTINUATION	$31,550
														Subtotal = $315,486

Issue Date FY: 2020 ( Subtotal = $316,363 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	16	2/13/2020	NON-COMPETING CONTINUATION	$31,637
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	11/26/2019	NON-COMPETING CONTINUATION	$284,726
2020	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	11/26/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $316,363

Issue Date FY: 2019 ( Subtotal = $337,137 )
2019	2019	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	004	14	9/4/2019	NON-COMPETING CONTINUATION	-$1
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	15	9/4/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$138,278
2019	2019	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	001	14	8/22/2019	NON-COMPETING CONTINUATION	-$292,632
2019	2019	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	12/3/2018	NON-COMPETING CONTINUATION	$292,633
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	15	8/22/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$337,136
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	003	13	9/4/2019	COMPETING CONTINUATION	-$138,277
														Subtotal = $337,137

Issue Date FY: 2018 ( Subtotal = $297,219 )
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	001	13	12/5/2017	COMPETING CONTINUATION	$297,219
2018	2016	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	12	3/29/2018	NON-COMPETING CONTINUATION	$0
2018	2016	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	11/30/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $297,219

Issue Date FY: 2016 ( Subtotal = $193,513 )
2016	2016	TEXAS A&M UNIVERSITY HEALTH SCIENCE CENTER	301 Tarrow	COLLEGE STATION	TX	77840	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	6/23/2016	NON-COMPETING CONTINUATION	$193,513
														Subtotal = $193,513

Issue Date FY: 2015 ( Subtotal = $193,513 )
2015	2015	TEXAS A&M UNIVERSITY HEALTH SCIENCE CENTER	301 Tarrow	COLLEGE STATION	TX	77840	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	7/15/2015	NON-COMPETING CONTINUATION	$193,513
														Subtotal = $193,513

Issue Date FY: 2014 ( Subtotal = $200,013 )
2014	2014	TEXAS A&M UNIVERSITY HEALTH SCIENCE CENTER	301 Tarrow	COLLEGE STATION	TX	77840	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	8/21/2014	COMPETING CONTINUATION	$200,013
														Subtotal = $200,013

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2010	TEXAS A & M RESEARCH FOUNDATION	400 Harvey Mitchell Parkway S,	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	6/18/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = -$9,230 )
2011	2010	TEXAS A & M RESEARCH FOUNDATION	400 Harvey Mitchell Parkway S,	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	9/22/2011	NON-COMPETING CONTINUATION	-$9,230
														Subtotal = -$9,230

Issue Date FY: 2010 ( Subtotal = $262,736 )
2010	2010	TEXAS A & M RESEARCH FOUNDATION	400 Harvey Mitchell Parkway S,	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/23/2010	NON-COMPETING CONTINUATION	$262,736
														Subtotal = $262,736

Issue Date FY: 2009 ( Subtotal = $265,371 )
2009	2009	TEXAS A & M RESEARCH FOUNDATION	400 Harvey Mitchell Parkway S,	COLLEGE STATION	TX	77845	BRAZOS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	7/28/2009	NON-COMPETING CONTINUATION	$265,371
														Subtotal = $265,371

Issue Date FY: 2008 ( Subtotal = $265,353 )
2008	2008	TEXAS A & M UNIVERSITY RESEARCH FOUNDATION	400 Harvey Mitchell Parkway S,	COLLEGE STATION	TX	77845	BRAZOS	USA	Digestive Diseases and Nutrition Research	000	7	8/6/2008	NON-COMPETING CONTINUATION	$265,353
														Subtotal = $265,353

Issue Date FY: 2007 ( Subtotal = $280,762 )
2007	2007	TEXAS A & M UNIVERSITY RESEARCH FOUNDATION	POST OFFICE BOX 3578	COLLEGE STATION	TX	77843	BRAZOS	USA	Digestive Diseases and Nutrition Research	000	6	8/2/2007	COMPETING CONTINUATION	$280,762
														Subtotal = $280,762

Issue Date FY: 2004 ( Subtotal = $174,089 )
2004	2004	TEXAS A & M UNIVERSITY RESEARCH FOUNDATION	POST OFFICE BOX 3578	COLLEGE STATION	TX	77843	BRAZOS	USA	Digestive Diseases and Nutrition Research	000	5	8/4/2004	NON-COMPETING CONTINUATION	$174,089
														Subtotal = $174,089

Issue Date FY: 2003 ( Subtotal = $174,089 )
2003	2003	TEXAS A & M UNIVERSITY RESEARCH FOUNDATION	POST OFFICE BOX 3578	COLLEGE STATION	TX	77843	BRAZOS	USA	Digestive Diseases and Nutrition Research	000	4	8/18/2003	NON-COMPETING CONTINUATION	$174,089
														Subtotal = $174,089

Issue Date FY: 2002 ( Subtotal = $174,089 )
2002	2002	TEXAS A & M UNIVERSITY RESEARCH FOUNDATION	POST OFFICE BOX 3578	COLLEGE STATION	TX	77843	BRAZOS	USA	Digestive Diseases and Nutrition Research	000	3	8/19/2002	NON-COMPETING CONTINUATION	$174,089
														Subtotal = $174,089

Issue Date FY: 2001 ( Subtotal = $174,089 )
2001	2001	TEXAS A & M UNIVERSITY RESEARCH FOUNDATION	POST OFFICE BOX 3578	COLLEGE STATION	TX	77843	BRAZOS	USA	Digestive Diseases and Nutrition Research	000	2	8/22/2001	NON-COMPETING CONTINUATION	$174,089
														Subtotal = $174,089

Issue Date FY: 2000 ( Subtotal = $185,089 )
2000	2000	TEXAS A & M RESEARCH FOUNDATION	400 Harvey Mitchell Parkway S,	COLLEGE STATION	TX	77845	BRAZOS	USA	Digestive Diseases and Nutrition Research	000	1	8/25/2000	NEW	$185,089
														Subtotal = $185,089

Grand Total All Awards = $3,796,801

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Growth Regulation of the Intrahepatic Biliary Tree

Award Number: R01DK054811

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: 09/01/2000

PERIOD OF PERFORMANCE END DATE: 11/30/2022

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