Saturday, December 2, 2023 12/2/2023

MECHANISTIC UNDERSTANDING OF PROTEIN INTERACTIONS AT THE TIGHT JUNCTION: STRUCTURAL REGULATION OF CANONICAL AND NONCANONICAL FUNCTIONS

Award Number: R01DK061931
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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SUMMARY Barrier function is compromised in infectious and immune-mediated intestinal and systemic diseases. This program, now completing its fourth funding cycle, has been guided by our long-term goal of understanding intestinal epithelial barrier regulation at a fundamental, molecular level and defining how regulation and dysregulation impact disease. This knowledge is required for development of rational, mechanism-based therapeutic approaches. In previous cycles, we have made paradigm-shifting discoveries including recognition that continuous molecular remodeling occurs within the tight junction. This and other new insight provided by our previous work led us to explore the molecular interactions and functional consequences of protein interactions at tight junctions. Our preliminary data demonstrate novel activities of claudin-4, occludin, and ZO- 1 that are unrelated to their ability to form tight junctions. Using a structural approach, we have discovered that occludin tail phosphorylation masks the ZO-1 binding site, while dephosphorylation triggers conformational change that enhances binding to ZO-1. The resulting occludin/ZO-1 complexed then form stable interactions with claudin-2, which disrupt channel function. In vivo, we found that the severity of immune-mediated colitis was markedly reduced or increased in claudin-2 knockout or transgenic mice, respectively. We combined the in vitro structural and in vivo functional data to inhibit occludin phosphorylation, block claudin-2 channels, and attenuate immune-mediated colitis in vivo. While exploring the potential of claudin-4 overexpression as a therapeutic intervention to enhance barrier function we found that neither knockout nor overexpression of claudin-4 affected tight junction permeability. Claudin-4 was, however, able to enhance barrier function when expressed along with claudin-2. These and other preliminary data indicate that, contrary to conventional wisdom, claudin-4 does not form barriers, but rather reduces permeability by directly disrupting claudin-2 polymers. Our patch-clamp studies showing that tight junction channels are actively gated suggest that less extreme approaches to modifying permeability, such as stabilizing the closed state of the channel, are possible. More nuanced approaches could be therapeutically important, as our in vivo studies indicate that complete claudin-2 channel inhibition can be detrimental. For example, loss of claudin-2-mediated paracellular water and Na+ efflux resulted in defective pathogen clearance by claudin-2 knockout mice. Separate studies of occludin led to our unexpected observation that, by mechanisms unrelated to barrier function, occludin is a key regulator of epithelial survival. In parallel we discovered that ZO-1 is required for epithelial orientation, proliferation, and apical structure. These data make it clear that studying these proteins individually will lead to incomplete understanding and will limit utility of the findings. This proposal therefore seeks to understand the relationships between diverse tight junction protein functions, the molecular interactions that direct these activities, and the potential of that knowledge to guide development of structure-based, rational therapies.


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 = $770,611 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	6/14/2023	NON-COMPETING CONTINUATION	$770,611


Issue Date FY: 2022 ( Subtotal = $770,611 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	7/8/2022	NON-COMPETING CONTINUATION	$770,611


Issue Date FY: 2021 ( Subtotal = $770,611 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	21	6/30/2021	NON-COMPETING CONTINUATION	$770,611
2021	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	20	6/4/2021	COMPETING CONTINUATION	$87,172
2021	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	6/4/2021	NON-COMPETING CONTINUATION	-$87,172


Issue Date FY: 2020 ( Subtotal = $790,361 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	5/19/2020	COMPETING CONTINUATION	$790,361


Issue Date FY: 2019 ( Subtotal = $651,399 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	6/25/2019	NON-COMPETING CONTINUATION	$651,399


Issue Date FY: 2018 ( Subtotal = $651,399 )
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	6/5/2018	NON-COMPETING CONTINUATION	$651,399


Issue Date FY: 2017 ( Subtotal = $651,399 )
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	17	6/21/2017	NON-COMPETING CONTINUATION	$651,399
2017	2016	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	16	3/20/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$79
2017	2015	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	3/20/2017	COMPETING CONTINUATION	$79
2017	2015	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	15	3/20/2017	COMPETING CONTINUATION	-$79
2017	2014	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	3/20/2017	NON-COMPETING CONTINUATION	-$79


Issue Date FY: 2016 ( Subtotal = $658,915 )
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	9/14/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$658,915


Issue Date FY: 2015 ( Subtotal = $612,412 )
2015	2015	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	6/9/2015	COMPETING CONTINUATION	$612,412


Issue Date FY: 2014 ( Subtotal = $565,297 )
2014	2014	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	6/5/2014	NON-COMPETING CONTINUATION	$565,297


Issue Date FY: 2013 ( Subtotal = $545,512 )
2013	2013	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	7/30/2013	NON-COMPETING CONTINUATION	$545,512


Issue Date FY: 2012 ( Subtotal = $565,297 )
2012	2012	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	6/28/2012	NON-COMPETING CONTINUATION	$565,297


Issue Date FY: 2011 ( Subtotal = $658,854 )
2011	2011	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	7/28/2011	COMPETING CONTINUATION	$658,854


Issue Date FY: 2010 ( Subtotal = $406,715 )
2010	2010	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	7/20/2010	SUPPLEMENT FOR EXPANSION	$95,810
2010	2010	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	6/18/2010	NON-COMPETING CONTINUATION	$310,905


Issue Date FY: 2009 ( Subtotal = $370,384 )
2009	2009	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	6/24/2009	NON-COMPETING CONTINUATION	$314,046
2009	2009	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Trans-NIH Recovery Act Research Support	000	8	7/14/2009	SUPPLEMENT FOR EXPANSION	$56,338


Issue Date FY: 2008 ( Subtotal = $314,046 )
2008	2008	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Digestive Diseases and Nutrition Research	000	8	6/17/2008	NON-COMPETING CONTINUATION	$314,046


Issue Date FY: 2007 ( Subtotal = $337,520 )
2007	2007	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Digestive Diseases and Nutrition Research	001	6	6/4/2007	SUPPLEMENT FOR EXPANSION	$17,066
2007	2007	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Digestive Diseases and Nutrition Research	000	7	7/3/2007	NON-COMPETING CONTINUATION	$320,454


Issue Date FY: 2006 ( Subtotal = $327,875 )
2006	2006	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Digestive Diseases and Nutrition Research	000	6	1/16/2006	COMPETING CONTINUATION	$327,875


Issue Date FY: 2005 ( Subtotal = $297,648 )
2005	2005	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Digestive Diseases and Nutrition Research	000	5	6/30/2005	NON-COMPETING CONTINUATION	$297,648


Issue Date FY: 2004 ( Subtotal = $297,648 )
2004	2004	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Digestive Diseases and Nutrition Research	000	4	6/21/2004	NON-COMPETING CONTINUATION	$297,648


Issue Date FY: 2003 ( Subtotal = $297,648 ) (Continued on the next page)
Grand Total All Awards = $11,937,130

Sum of Action Amount is $11,937,130;

Grand Total = $11,937,130

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MECHANISTIC UNDERSTANDING OF PROTEIN INTERACTIONS AT THE TIGHT JUNCTION: STRUCTURAL REGULATION OF CANONICAL AND NONCANONICAL FUNCTIONS

Award Number: R01DK061931

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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