Monday, June 30, 2025 6/30/2025

Pathobiology of Hepatic Epithelia

Award Number: R01DK024031
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: 12/01/1978
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Pathobiology of Hepatic Epithelia - PROJECT SUMMARY/ABSTRACT Our GOALS are to continue to clarify the pathogenesis of polycystic liver disease (PLD) and develop effective therapies. PLD is a genetic ciliopathy for which there are no regulatory approved drugs. We reported that PLD cholangiocytes (PLDC) have increased cAMP, accelerated autophagy, and structurally and functionally malformed cilia. However, it remains unclear what mechanisms are involved, how they contribute to hepatic cystogenesis, or if they represent new therapeutic targets. Based on recent published observations and our preliminary data, our OVERALL OBJECTIVES are to explore the mechanistic relations between autophagy of ciliogenic proteins (i.e., proteins involved in cilia maintenance), pro-cystogenic signaling and hepatic cystogenesis. Our preliminary data show: i) autophagy, cilia, and cAMP signaling are the most altered biological processes in human PLDC vs. normal cholangiocytes (NHC) as assessed by RNAseq and gene enrichment analysis; ii) ciliogenic proteins are diminished in PLDC cilia but increased in autophagosomes isolated from PLDC; iii) in PLDC, HDAC6 is increased and ubiquitinates ciliogenic proteins; iv) in PLDC, the G- protein coupled bile acid receptor, TGR5, is depleted in cilia due to autophagic degradation of ciliogenic proteins that normally target TGR5 to cilia, is overexpressed at the apical membrane and its activation further increases cAMP; and v) genetic elimination of the ciliogenic protein, Kif3A, from cholangiocytes in mice leads to malformed TGR5-depleted cilia, TGR5 overexpression at the apical membrane, and hepatic cystogenesis. Thus, our data support the CENTRAL HYPOTHESIS that in PLD, HDAC6-dependent autophagy of ciliogenic proteins disrupts ciliogenesis resulting in malformed cholangiocyte cilia, ciliary depletion of TGR5, enhanced pro-cystogenic signaling and hepatic cyst growth. We will test this hypothesis by using biochemical, molecular and microscopic techniques, cultured and freshly isolated human and rodent normal and PLD cholangiocytes, unique animal models, and human tissue. Our proposal has three integrated SPECIFIC AIMS. First, we test the hypothesis that autophagy-mediated, HDAC6-dependent depletion of ciliogenic proteins disrupts ciliogenesis in PLDC resulting in malformed cilia. Second, we test the hypothesis that autophagy of ciliogenic proteins depletes cholangiocyte cilia of TGR5 and enhances pro-cystogenic signaling and cyst growth. Third, we test the hypothesis that pharmacologic interventions that target cholangiocyte autophagy and ciliogenesis (ciliotherapy) inhibit cystogenesis in vitro and in animal models of PLD. These innovative experiments will: i) clarify how autophagy of ciliogenic proteins leads to ciliary malformations; ii) address how HDAC6-mediated autophagy of ciliogenic proteins disrupts ciliary targeting of TGR5, thereby increasing pro-cystogenic cAMP signaling and cyst growth; and iii) explore how pharmacologic manipulations of autophagy and ciliogenesis affect cystogenesis (ciliotherapy). Our results will be informative for mechanisms of PLD progression and potentially transformative for new therapeutic approaches.


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: 2024 ( Subtotal = $0 )
2024	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	43	8/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $357,750 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	43	3/30/2023	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2022 ( Subtotal = $357,750 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	42	3/24/2022	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2021 ( Subtotal = $357,750 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	41	3/23/2021	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2020 ( Subtotal = $357,750 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	40	6/23/2020	COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	39	10/23/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $473,780 )
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	39	3/23/2017	NON-COMPETING CONTINUATION	$426,402
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	39	6/16/2017	NON-COMPETING CONTINUATION	$47,378
														Subtotal = $473,780

Issue Date FY: 2016 ( Subtotal = $473,780 )
2016	2016	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	38	2/26/2016	NON-COMPETING CONTINUATION	$473,780
														Subtotal = $473,780

Issue Date FY: 2015 ( Subtotal = $473,780 )
2015	2015	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	37	3/20/2015	NON-COMPETING CONTINUATION	$473,780
														Subtotal = $473,780

Issue Date FY: 2014 ( Subtotal = $473,780 )
2014	2014	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	36	6/20/2014	COMPETING CONTINUATION	$473,780
														Subtotal = $473,780

Issue Date FY: 2013 ( Subtotal = $550,976 )
2013	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	35	3/14/2013	NON-COMPETING CONTINUATION	$513,865
2013	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	35	5/20/2013	NON-COMPETING CONTINUATION	$37,111
														Subtotal = $550,976

Issue Date FY: 2012 ( Subtotal = $570,959 )
2012	2012	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	34	4/6/2012	NON-COMPETING CONTINUATION	$570,959
														Subtotal = $570,959

Issue Date FY: 2011 ( Subtotal = $559,836 )
2011	2011	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	33	5/27/2011	NON-COMPETING CONTINUATION	-$16,774
2011	2011	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	33	5/25/2011	NON-COMPETING CONTINUATION	$52,418
2011	2011	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	33	3/23/2011	NON-COMPETING CONTINUATION	$524,192
														Subtotal = $559,836

Issue Date FY: 2010 ( Subtotal = $624,424 )
2010	2010	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	32	4/15/2010	NON-COMPETING CONTINUATION	$624,424
														Subtotal = $624,424

Issue Date FY: 2009 ( Subtotal = $616,490 )
2009	2009	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	31	3/27/2009	COMPETING CONTINUATION	$616,490
														Subtotal = $616,490

Issue Date FY: 2008 ( Subtotal = $503,420 )
2008	2008	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55901	OLMSTED	USA	Digestive Diseases and Nutrition Research	000	30	3/20/2008	NON-COMPETING CONTINUATION	$503,420
														Subtotal = $503,420

Issue Date FY: 2007 ( Subtotal = $502,208 )
2007	2007	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55901	OLMSTED	USA	Digestive Diseases and Nutrition Research	000	29	3/15/2007	NON-COMPETING CONTINUATION	$502,208
														Subtotal = $502,208

Issue Date FY: 2006 ( Subtotal = $502,732 )
2006	2006	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55901	OLMSTED	USA	Digestive Diseases and Nutrition Research	000	28	4/14/2006	NON-COMPETING CONTINUATION	$502,732
														Subtotal = $502,732

Issue Date FY: 2005 ( Subtotal = $499,835 )
2005	2005	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55901	OLMSTED	USA	Digestive Diseases and Nutrition Research	000	27	6/6/2005	NON-COMPETING CONTINUATION	$499,835
														Subtotal = $499,835

Issue Date FY: 2004 ( Subtotal = $485,275 )
2004	2004	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55901	OLMSTED	USA	Digestive Diseases and Nutrition Research	000	26	8/15/2004	COMPETING CONTINUATION	$485,275
														Subtotal = $485,275

Issue Date FY: 2003 ( Subtotal = $432,203 )
2003	2003	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55901	OLMSTED	USA	Digestive Diseases and Nutrition Research	000	25		NON-COMPETING CONTINUATION	$432,203
														Subtotal = $432,203

Issue Date FY: 2002 ( Subtotal = $422,258 )
2002	2002	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55901	OLMSTED	USA	Digestive Diseases and Nutrition Research	000	24	4/4/2002	NON-COMPETING CONTINUATION	$422,258
														Subtotal = $422,258

Issue Date FY: 2001 ( Subtotal = $412,603 )
2001	2001	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55901	OLMSTED	USA	Digestive Diseases and Nutrition Research	000	23	3/14/2001	NON-COMPETING CONTINUATION	$412,603
														Subtotal = $412,603

Grand Total All Awards = $10,810,931

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Pathobiology of Hepatic Epithelia

Award Number: R01DK024031

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: 12/01/1978

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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