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Inhibition of an Apical cAMP/cGMP Transporter (MRP4) in the Gut Induces Diarrhea

Award Number: R01DK080834
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: 08/20/2009
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Inhibition of an Apical cAMP/cGMP Transporter (MRP4) in the Gut Induces Diarrhea - Most patients with cystic fibrosis (CF) experience a range of gastrointestinal (GI) complications. Meconium ileus is present in about 10% of CF newborns. Later in life, the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel activity causes impairment in intestinal fluid secretion and homeostasis, contributing to the development of constipation, distal intestinal obstruction, and other GI diseases. In addition to CF patients, chronic constipation affects approximately 2-27% of general population worldwide; it is one of the most common GI issues in geriatric population. In this proposal, we will address these two health issues. Based on our previous findings and preliminary data, we hypothesize that (i) the impairment in intestinal fluid secretion and homeostasis plays a critical role in the pathogenic process of chronic constipation in CF patients and in geriatric population. (ii) CFTR-MRP4 complexes and the associated secretory mechanisms are impaired in these two populations. And (iii) the CFTR-MRP4 complexes can be targeted to restore the impaired secretion and alleviate/cure chronic constipation. Three specific aims were designed to test our hypothesis: (1) test the regulatory role of CFTR-MRP4 macromolecular complexes in compartmentalized cAMP/cGMP signaling and in the CFTR-mediated fluid secretion using intestinal stem cells (ISCs) cultures from CF patients with chronic constipation. (2) test the effects of the current FDA-approved highly effective CFTR modulator therapies (e.g., Kalydeco® and Trikafta®) and MRP4 inhibitors on intestinal fluid secretion in enteroids from CF patients with chronic constipation, and study if these two types of modulators have additive or synergistic effect. And (3) test if the CFTR-dependent fluid secretion in aged mouse gut is impaired which contributes to chronic constipation and investigate the underlying molecular mechanism. Our proposal incorporates both conceptual and technical innovations that will not only advance our understanding of disease pathogenesis of chronic constipation in CF patients and in large ageing populations, but also help identify possible therapeutic targets for interventions. We will use patient-derived and clinically relevant samples and adopt a personalized medicine platform: a Bench to Bedside and Back approach, which warrant a high potential to translate our bench-side findings to clinical disease management.


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 = $579,373 )
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	18	5/30/2025	NON-COMPETING CONTINUATION	$579,373
2025	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	2/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $579,373

Issue Date FY: 2024 ( Subtotal = $606,584 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	5/21/2024	COMPETING CONTINUATION	$606,584
														Subtotal = $606,584

Issue Date FY: 2022 ( Subtotal = $407,440 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	16	6/23/2022	NON-COMPETING CONTINUATION	$375,451
2022	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	1/12/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$392,507
2022	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	1/11/2022	NON-COMPETING CONTINUATION	-$360,518
2022	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	15	6/6/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$34,776
2022	2020	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	13	6/6/2022	NON-COMPETING CONTINUATION	-$34,776
														Subtotal = $407,440

Issue Date FY: 2021 ( Subtotal = $360,518 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	5/21/2021	NON-COMPETING CONTINUATION	$360,518
														Subtotal = $360,518

Issue Date FY: 2020 ( Subtotal = $360,518 )
2020	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	5/8/2020	NON-COMPETING CONTINUATION	$360,518
														Subtotal = $360,518

Issue Date FY: 2019 ( Subtotal = $360,518 )
2019	2019	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	5/22/2019	NON-COMPETING CONTINUATION	$360,518
														Subtotal = $360,518

Issue Date FY: 2018 ( Subtotal = $373,793 )
2018	2018	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	11	9/21/2018	COMPETING CONTINUATION	$15,365
2018	2018	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	6/15/2018	COMPETING CONTINUATION	$373,793
2018	2017	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	10	9/21/2018	NON-COMPETING CONTINUATION	-$15,365
2018	2017	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	6/12/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $373,793

Issue Date FY: 2017 ( Subtotal = $333,363 )
2017	2017	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	3/14/2017	NON-COMPETING CONTINUATION	$300,025
2017	2017	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	6/15/2017	NON-COMPETING CONTINUATION	$33,338
														Subtotal = $333,363

Issue Date FY: 2016 ( Subtotal = $333,536 )
2016	2016	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	3/15/2016	NON-COMPETING CONTINUATION	$333,536
														Subtotal = $333,536

Issue Date FY: 2015 ( Subtotal = $340,664 )
2015	2015	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	3/2/2015	NON-COMPETING CONTINUATION	$340,664
														Subtotal = $340,664

Issue Date FY: 2014 ( Subtotal = $355,250 )
2014	2014	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	3/6/2014	NON-COMPETING CONTINUATION	$346,640
2014	2013	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/12/2013	COMPETING CONTINUATION	-$215,238
2014	2013	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	12/12/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$223,848
														Subtotal = $355,250

Issue Date FY: 2013 ( Subtotal = $341,712 )
2013	2013	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	6	12/12/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$223,848
2013	2013	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	12/12/2013	COMPETING CONTINUATION	-$215,238
2013	2013	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	2/18/2013	COMPETING CONTINUATION	$333,102
2013	2012	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/14/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $341,712

Issue Date FY: 2012 ( Subtotal = $316,253 )
2012	2012	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/10/2012	NON-COMPETING CONTINUATION	$316,253
														Subtotal = $316,253

Issue Date FY: 2011 ( Subtotal = $319,144 )
2011	2011	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/25/2011	NON-COMPETING CONTINUATION	$29,013
2011	2011	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/17/2010	NON-COMPETING CONTINUATION	$290,131
														Subtotal = $319,144

Issue Date FY: 2010 ( Subtotal = $362,371 )
2010	2010	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/26/2010	NON-COMPETING CONTINUATION	$362,371
														Subtotal = $362,371

Issue Date FY: 2009 ( Subtotal = $436,234 )
2009	2009	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/24/2008	NEW	$330,309
2009	2009	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	3/20/2009	NEW	$34,170
2009	2009	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Trans-NIH Recovery Act Research Support	002	1	8/12/2009	SUPPLEMENT FOR EXPANSION	$71,755
														Subtotal = $436,234

Grand Total All Awards = $6,187,271

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Inhibition of an Apical cAMP/cGMP Transporter (MRP4) in the Gut Induces Diarrhea

Award Number: R01DK080834

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: 08/20/2009

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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