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Cell-cell adhesion-mediated signaling determines epithelial polarization in the liver

Award Number: R01DK118015
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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NOTE: You must submit in Word format, not PDF, for eRA to update all the systems. The liver is our largest metabolic organ. It produces proteins, lipids, clotting factors and glycogen while dispensing bile and detoxifying xenobiotics. In order to transport these different substances, a sophisticated network of liver venules, capillaries and interstitial conduits has evolved. An essential feature of this network are the lumen-forming epithelia that give rise to two major liver cell populations: (1) hepatocytes - the main parenchymal cell type, and (2) bile duct cells. Both acquire radically different polarity phenotypes adapted to their different functions (Fig.1): Bile duct cells, which form simple conduits for bile, organize like other tubular epithelia around a central lumen. Hepatocytes, by contrast form single-cell cords, aligned along blood vessels on either side and with a capillary-like luminal network (bile canaliculi) running between them. This organization facilitates their extensive bi-directional molecular exchange with the blood, while allowing bile acid excretion into the bile canaliculi. How hepatocytes obtain this unique morphological phenotype is poorly understood. Indeed, because bile canaliculi are not visible by conventional H&E tissue stain, the study of hepatocyte polarity has largely been neglected. The resulting gap in our knowledge has greatly hindered our ability to better understand the molecular basis of common liver diseases, which typically present with changes in hepatocyte polarity and morphology. It also severely limits our ongoing efforts to engineer hepatic tissue that can be used for transplantation, toxicology and gene therapy studies. To tackle these issues, we developed a unique tissue culture model in which the polarity phenotype can be switched from ductal to hepatocytic and utilized it to identify molecular mechanisms that distinguish the hepatocytic from the ductal polarization program. In parallel, we developed protocols to in vitro differentiate polarized hepatocytes from their precursors and evaluated proteins critical for the hepatocytic polarity switch in these physiological relevant systems. This led to the discovery of the dual PKA-anchoring and Rho-activating protein AKAP13 as regulator of bile canaliculi elongation. Elucidating the mechanisms underlying its function, as proposed here, will reveal a critical morphological mechanisms of hepatocyte polarization.


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 = $384,000 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	7/1/2024	NON-COMPETING CONTINUATION	$384,000
2024	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	7/18/2024	COMPETING CONTINUATION	$16,731
2024	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	7/18/2024	NON-COMPETING CONTINUATION	-$16,731
														Subtotal = $384,000

Issue Date FY: 2023 ( Subtotal = $400,000 )
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	7/17/2023	NON-COMPETING CONTINUATION	$400,000
2023	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	10/31/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $400,000

Issue Date FY: 2022 ( Subtotal = $400,000 )
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	8/8/2022	COMPETING CONTINUATION	$400,000
2022	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $400,000

Issue Date FY: 2021 ( Subtotal = $589,839 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/19/2021	NON-COMPETING CONTINUATION	$589,839
														Subtotal = $589,839

Issue Date FY: 2020 ( Subtotal = $589,839 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/19/2020	NON-COMPETING CONTINUATION	$589,839
														Subtotal = $589,839

Issue Date FY: 2019 ( Subtotal = $589,839 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/4/2019	NEW	$589,839
														Subtotal = $589,839

Grand Total All Awards = $2,953,517

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Cell-cell adhesion-mediated signaling determines epithelial polarization in the liver

Award Number: R01DK118015

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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