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Linkage of s100a10 (p11) to enteric 5-HT4-mediated serotonergic signaling roles in GI motility, enteric nervous system development, and co-morbid dysfunction of gut and brain

Award Number: R01DK126644
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: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Linkage of s100a10 (p11) to enteric 5-HT4-mediated serotonergic signaling roles in GI motility, enteric nervous system development, and co-morbid dysfunction of gut and brain - Project Summary Although functional gastrointestinal (GI) disorders (FGIDs) are the most common causes of bowel dysfunction worldwide, many patients are inadequately treated because current therapies are frequently ineffective. The inadequacy of therapy is largely due to an incomplete comprehension of underlying mechanisms that are critical for the design of new treatments. Up to half of individuals with FGIDs also suffer from mood disorders. Evidence supports the idea that the GI tract is vulnerable to genetic perturbations that can exert lasting effects on GI function and mood. It is thus conceivable that a co-morbid FGID and psychiatric condition result from abnormalities occurring as the result of a genetic variant. Discovery of the pathophysiology underlying FGIDs and psychiatric co-morbidities is likely to enhance understanding of their relationship and thus lead to novel therapies for both. Serotonin (5-HT), which is a major determinant of enteric and central nervous system (ENS and CNS) development and also modulates FGID-related symptoms (GI motility) as well as mood, may be an important developmental modulator of FGID pathogenesis. It is 5-HT stimulation of the 5-HT4 receptor, however, that has the most well-studied prokinetic, anti-nociceptive, anti- depressive, and anti-anxiety effects and has thus been targeted to treat both GI dysmotility and mood dysfunction. Curiously, however, >50% of patients with FGIDs are relatively unresponsive to them. The reason for 5-HT4 treatment failure is unknown, making this a critical treatment obstacle. Our preliminary data strongly suggest that failure to respond to a 5-HT4 agonist is due to a defect in 5-HT4 trafficking. Although defects in enteric 5-HT4 trafficking have never previously been explored, such abnormalities have been described in the CNS; p11 is a critical adaptor molecule involved in this transport of 5-HT4 receptors to cell surfaces, where the receptors become available to mediate 5-HT signaling. P11 also plays a role in depression (p11KO mice exhibit depressive behaviors and CNS p11 transcription is impaired in mouse models of depression and human suicide victims). We have found that in the ENS, as in the CNS, gut p11 is co- expressed with 5-HT4 receptors where they co-immunoprecipitate, suggesting that p11 interacts with 5-HT4 in the gut and, further, that p11 affects 5-HT4 receptor-mediated actions on ENS development and GI motility. Our hypotheses are thus that p11 facilitation of trafficking of 5-HT4 receptors to cell surfaces is essential for 5-HT4- modulation of ENS development and function and that p11 dysfunction thus underlies comorbid FGID and depression. In this application we will explore: (1) How critical the p11-5-HT4 interaction is for effective GI motility utilizing a comprehensive array of in vivo and ex vivo studies ± the selective 5-HT4 agonist, prucalopride, in WT and p11KO mice; (2) If effects of p11 on mood (depression / anxiety), ENS development, and GI motility depend on mucosal or enteric neuronal p11, using novel transgenic mice that selectively lack p11 in the enteric epithelium or ENS and; (3) If enteric 5-HT4 trafficking and function are p11-dependent.


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 = $444,808 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/10/2024	NON-COMPETING CONTINUATION	$27,802
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/25/2024	NON-COMPETING CONTINUATION	$417,006
														Subtotal = $444,808

Issue Date FY: 2023 ( Subtotal = $477,740 )
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	7/28/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$427,291
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$477,740
2023	2022	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	7/28/2023	NON-COMPETING CONTINUATION	-$427,291
2023	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $477,740

Issue Date FY: 2022 ( Subtotal = $487,100 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/29/2022	NON-COMPETING CONTINUATION	$48,710
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/19/2022	NON-COMPETING CONTINUATION	$438,390
														Subtotal = $487,100

Issue Date FY: 2021 ( Subtotal = $458,586 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/22/2021	NEW	$458,586
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	3/15/2021	NEW	$458,586
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	3/11/2021	NEW	-$458,586
														Subtotal = $458,586

Grand Total All Awards = $1,868,234

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Linkage of s100a10 (p11) to enteric 5-HT4-mediated serotonergic signaling roles in GI motility, enteric nervous system development, and co-morbid dysfunction of gut and brain

Award Number: R01DK126644

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: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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