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Therapeutic targeting of protein interactions to reverse MLCK1-mediated intestinal barrier loss and ameliorate disease.

Award Number: R01DK068271
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: 07/01/2005
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Therapeutic targeting of protein interactions to reverse MLCK1-mediated intestinal barrier loss and ameliorate disease. - SUMMARY Increased intestinal permeability, i.e., barrier loss, is a common characteristic of many gastrointestinal and systemic disorders and has been hypothesized to be a key contributor to disease progression. Animal models of disease provide strong support for this hypothesis, but, due to the absence of drugs that reverse disease- associated permeability increases, the therapeutic potential of intestinal barrier restoration is untested. Myosin light chain kinase (MLCK) is a signaling node that, when activated, increases permeability. In inflammatory bowel disease (IBD) patient biopsies, MLCK activity is upregulated and correlates with disease severity. Recent studies have shown that inflammatory stimuli trigger recruitment of a specific MLCK isoform, MLCK1, to the perijunctional cytoskeleton and that this MLCK1 recruitment is required for barrier loss. Further, disruption of the MLCK1 interactome that directs recruitment is therapeutically superior to anti-TNF in experimental IBD. Therefore, the long-term goal of this program is to create the detailed understanding that will enable development of agents that target the MLCK1 interactome to restore barrier function and benefit IBD patients. The overall objectives of this application are to i) discover the molecular basis of MLCK1 interactome function and ii) apply this knowledge to block MLCK1 recruitment in experimental IBD. The central hypothesis is that prevention of MLCK1 interactome-dependent recruitment can restore the intestinal barrier. The rationale for this project is that elucidating the molecular mechanisms of MLCK1 interactome function and assessing the preclinical efficacy of targeting interactome components will create the scientific foundation needed for translation to the clinic. The central hypothesis will be tested via three specific aims: i) define mechanisms that regulate interactions between MLCK1 interactome components and identify sites that can be targeted to disrupt these interactions; ii) determine how, when, and where these interactions are modified by inflammatory signals and the potential of obstructing key interactions as a means to block MLCK1 recruitment and restore barrier function in intestinal stem cell models; and iii) characterize the impact of interfering with dynamic regulation of the MLCK1 interactome in preclinical mouse models and assess interactome staus in patient biopsies. This proposal is conceptually and technically innovative because it will define function and regulation of the newly-recognized MLCK1 interactome using sophisticated in vitro and in vivo models as well as patient biopsies. These studies are significant because they are expected to create the structural and mechanistic insight required for development of molecular therapies that modify unique MLCK1 interactome functions to prevent or reverse barrier loss in IBD. Ultimately, advances that build on this critical information will create a foundation for development of safe, non-immunosuppressive means to restore the intestinal barrier and induce and maintain remission in IBD. These agents are also likely to provide benefit in other barrier loss- associated disorders, including celiac disease, food allergy, diabetes, and metabolic syndrome.


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: 2025 ( Subtotal = $760,807 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	20	7/31/2025	NON-COMPETING CONTINUATION	$760,807
2025	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	2/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $760,807

Issue Date FY: 2024 ( Subtotal = $780,557 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	7/11/2024	COMPETING CONTINUATION	$780,557
														Subtotal = $780,557

Issue Date FY: 2022 ( Subtotal = $688,227 )
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	18	7/1/2022	NON-COMPETING CONTINUATION	$688,227
														Subtotal = $688,227

Issue Date FY: 2021 ( Subtotal = $688,227 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	6/30/2021	NON-COMPETING CONTINUATION	$688,227
														Subtotal = $688,227

Issue Date FY: 2020 ( Subtotal = $688,227 )
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	16	7/1/2020	NON-COMPETING CONTINUATION	$688,227
														Subtotal = $688,227

Issue Date FY: 2019 ( Subtotal = $688,227 )
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	15	5/24/2019	COMPETING CONTINUATION	$688,227
														Subtotal = $688,227

Issue Date FY: 2018 ( Subtotal = $496,306 )
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	14	6/27/2018	NON-COMPETING CONTINUATION	$496,306
														Subtotal = $496,306

Issue Date FY: 2017 ( Subtotal = $496,306 )
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	6/22/2017	NON-COMPETING CONTINUATION	$496,306
														Subtotal = $496,306

Issue Date FY: 2016 ( Subtotal = $496,306 )
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	9/16/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$496,306
														Subtotal = $496,306

Issue Date FY: 2015 ( Subtotal = $470,052 )
2015	2015	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	6/4/2015	NON-COMPETING CONTINUATION	$470,052
														Subtotal = $470,052

Issue Date FY: 2014 ( Subtotal = $470,052 )
2014	2014	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	4/8/2014	COMPETING CONTINUATION	$470,052
														Subtotal = $470,052

Issue Date FY: 2013 ( Subtotal = $454,214 )
2013	2013	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	8/7/2013	NON-COMPETING CONTINUATION	$454,214
														Subtotal = $454,214

Issue Date FY: 2012 ( Subtotal = $472,473 )
2012	2012	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	6/29/2012	NON-COMPETING CONTINUATION	$472,473
														Subtotal = $472,473

Issue Date FY: 2011 ( Subtotal = $474,305 )
2011	2011	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	6/27/2011	NON-COMPETING CONTINUATION	$474,305
														Subtotal = $474,305

Issue Date FY: 2010 ( Subtotal = $655,566 )
2010	2010	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	7/12/2010	COMPETING CONTINUATION	$555,607
2010	2010	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Trans-NIH Recovery Act Research Support	000	5	12/3/2009	SUPPLEMENT FOR EXPANSION	$99,959
														Subtotal = $655,566

Issue Date FY: 2009 ( Subtotal = $333,010 )
2009	2009	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/6/2009	NON-COMPETING CONTINUATION	$333,010
														Subtotal = $333,010

Issue Date FY: 2008 ( Subtotal = $333,010 )
2008	2008	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Digestive Diseases and Nutrition Research	000	4	6/4/2008	NON-COMPETING CONTINUATION	$333,010
														Subtotal = $333,010

Issue Date FY: 2007 ( Subtotal = $339,805 )
2007	2007	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Digestive Diseases and Nutrition Research	000	3	6/29/2007	NON-COMPETING CONTINUATION	$339,805
														Subtotal = $339,805

Issue Date FY: 2006 ( Subtotal = $349,954 )
2006	2006	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Digestive Diseases and Nutrition Research	000	2	6/23/2006	NON-COMPETING CONTINUATION	$349,954
														Subtotal = $349,954

Issue Date FY: 2005 ( Subtotal = $358,375 )
2005	2005	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Digestive Diseases and Nutrition Research	000	1	3/7/2005	NEW	$358,375
														Subtotal = $358,375

Grand Total All Awards = $10,494,006

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Therapeutic targeting of protein interactions to reverse MLCK1-mediated intestinal barrier loss and ameliorate disease.

Award Number: R01DK068271

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: 07/01/2005

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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