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Primary cilia loss in bile duct cells- the interplay with the autophagy machinery

Award Number: R01DK132781
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: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Primary cilia loss in bile duct cells- the interplay with the autophagy machinery - Project Summary/Abstract Primary cilia are multisensory organelles that function as cellular antennae. We found that ciliary defects in cholangiocytes and/or the loss of primary cilia are associated with biliary tract diseases like polycystic liver disease (PLD) and cholangiocarcinoma (CCA). A better understanding of the signaling regulated by cilia and mechanisms of ciliary loss in diseased cholangiocytes is critical to design new therapies based on the restoration of cilia, i.e. ciliotherapies. Our current overall objective is to understand the role of cilia in the regulation of epidermal growth factor receptor (EGFR) signaling. EGFR signaling is abnormally persistent and enhanced in PLD and CCA, two diseases with ciliary dysfunction. Furthermore, we aim to explore the mechanisms of ciliary loss in cholangiocytes – especially how the autophagy machinery is targeted to resorption of this organelle. This proposal will assess how cilia-autophagy communication works in cholangiocytes to reduce ciliary expression and, consequently, how the loss or dysfunction of cilia enhances EGFR signaling. We propose that pathologically-induced ciliophagy accounts for ciliary loss/dysfunction, inducing sustained EGFR signaling. We propose three Specific Aims: In Specific Aim 1: To characterize molecular mechanisms of the ciliary-dependent degradation of activated EGFR, we will assess the need of cilia for activated EGFR degradation; characterize the mechanisms of EGFR translocation to primary cilia; and assess the hypothesis that the E3 ubiquitin ligase c-CBL translocates to the primary cilia upon EGF signaling and drives the degradation of activated EGFR located in the cilia. In Specific Aim 2: To identify the key players involved in targeting ciliary components to the autophagy machinery, we will assess the role of autophagy and HDAC6/SIRT1 in ciliary expression in vitro; assess the role of HDAC6/SIRT1 in ciliophagy in vivo; study the interaction between ciliary proteins and autophagy cargo receptors; and test the hypothesis that in ciliary-defective cholangiocytes, overexpression of deacetylases induces lysine deacetylation of ciliary components, which leads to ubiquitination of the same residues and targeting of the autophagy machinery by specific autophagy cargo receptors. In Specific Aim 3: To test the combination of specific deacetylases, autophagy, and EGFR inhibitors in pre-clinical rodent models as a therapeutic approach, we will assess the effect of HDAC6 inhibition (Tubastatin-A or ACY-1215), and/or SIRT1 inhibition (Sirtinol) in combination with autophagy inhibitors (e.g., HCQ, SAR405) with or without EGFR inhibition (Erlotinib, Afatinib) in vitro and in vivo; assess the in vivo effects of Ciliomax (a novel dual inhibitor we recently developed) plus EGFR inhibition; and assess the most promising treatments in patient-derived xenografts. Impact: identifying novel targets could lead to much-needed new therapeutic strategies for these devastating diseases. Our experiments in in vitro and pre-clinical rodent models will characterize the ciliary-dependent regulation of EGFR and the communication between primary cilia and the autophagy process, which will lay the foundation for potential clinical trials.


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: 2026 ( Subtotal = $481,610 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/14/2026	NON-COMPETING CONTINUATION	$481,610
														Subtotal = $481,610

Issue Date FY: 2025 ( Subtotal = $487,260 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/14/2025	NON-COMPETING CONTINUATION	$48,725
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/20/2025	NON-COMPETING CONTINUATION	$438,535
														Subtotal = $487,260

Issue Date FY: 2024 ( Subtotal = $566,080 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	5/14/2024	SUPPLEMENT FOR EXPANSION	$9,513
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	5/13/2024	NON-COMPETING CONTINUATION	$29,436
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/26/2024	NON-COMPETING CONTINUATION	$441,516
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/29/2024	SUPPLEMENT FOR EXPANSION	$85,615
														Subtotal = $566,080

Issue Date FY: 2023 ( Subtotal = $561,771 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	9/4/2023	SUPPLEMENT FOR EXPANSION	$38,513
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	8/25/2023	SUPPLEMENT FOR EXPANSION	$29,436
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/24/2023	NEW	$493,822
														Subtotal = $561,771

Grand Total All Awards = $2,096,721

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Primary cilia loss in bile duct cells- the interplay with the autophagy machinery

Award Number: R01DK132781

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: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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