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Differences in Gastrointestinal Motility Between Males and Females in Health and Diabetes

Award Number: R01DK124269
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: 02/17/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Differences in Gastrointestinal Motility Between Males and Females in Health and Diabetes - Enter the text here that is the new abstract information for your application. Gastrointestinal (GI) motility differs between men and women. In women, GI motility varies with hormonal changes during the menstrual cycle and pregnancy. However, there is a gap in knowledge and understanding of the role of estrogen and the mechanisms by which it regulates differences in GI motility and dysmotility between males and cycling females. Unlike classical nuclear receptors ERα, ERβ, activation of membrane-bound G protein-coupled estrogen receptor (GPER) by estrogen initiates rapid cellular events. We have obtained preliminary evidence to show that GPER is expressed in smooth muscle and is coupled to AC/cAMP/PKA pathway to mediate muscle relaxation in the stomach and the colon. Smooth muscle from GPER KO mice exhibited loss of relaxation in response to GPER agonist, providing evidence for a role of GPER in smooth muscle relaxation. GI transit was delayed in female mice of high-estrogen proestrus and estrus phases compared to low-estrogen diestrus phase, and male mice. Differences in GI transit between males and cycling females, as well as cycle-dependent variations, are associated with changes in the expression and function of GPER. Based on these preliminary data, studies are proposed to test the hypothesis that differences in GI transit between males and females, as well as cycle-dependent changes are due to alterations in the expression and function of GPER coupled to activation of the AC/cAMP/PKA pathway and smooth muscle relaxation (Specific Aim 1). GI motility disorders also differ between men and women. There is a greater prevalence of diabetes-associated gastroparesis and constipation in women compared to men. The contribution of impaired smooth muscle function and the role of GPER in smooth muscle have not been fully explored in relation to differences between males and females in GI dysmotility associated with diabetes. Preliminary studies showed that expression of GPER was decreased in smooth muscle from diabetic mice and the decrease is mediated via oxidative stress-induced changes in epigenetic regulation via a decrease in trimethylation of H3 at lysine residue 4 (H3K4me3) and acetylation of H3 at lysine residue 27 (H3K27ac) at the promoter region of GPER gene. RNA-seq data combined with heatmap analysis showed an increase in the expression of selective histone deacetylase (HDACs) in smooth muscle from diabetic mice. An increase in oxidative stress was also obtained in smooth muscle from GPER KO mice suggesting the increase in oxidative stress in diabetes could be due to a decrease in GPER expression. Based on the preliminary data, studies ae proposed to test the hypothesis that an increase in oxidative stress in diabetes downregulates GPER expression via decrease in H3K4me3 and H3K27ac of GPER promoter, and loss of GPER-mediated protection against oxidative stress leads to decrease in cAMP/cGMP signaling, muscle relaxation and GI transit (Specific Aim 2). Our study elucidates the mechanisms underlying GI motility differences in males and cycling females. The higher prevalence of diabetes-associated GI dysmotility in females highlights the clinical importance of this research.


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 = $361,155 )
2025	2025	TUSKEGEE UNIVERSITY	1200 W MONTGOMERY RD	TUSKEGEE INSTITUTE	AL	36088	MACON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/4/2025	NON-COMPETING CONTINUATION	$361,155
														Subtotal = $361,155

Issue Date FY: 2024 ( Subtotal = $355,856 )
2024	2024	TUSKEGEE UNIVERSITY	1200 W MONTGOMERY RD	TUSKEGEE INSTITUTE	AL	36088	MACON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/15/2024	NON-COMPETING CONTINUATION	$22,240
2024	2024	TUSKEGEE UNIVERSITY	1200 W MONTGOMERY RD	TUSKEGEE INSTITUTE	AL	36088	MACON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/25/2024	NON-COMPETING CONTINUATION	$333,616
														Subtotal = $355,856

Issue Date FY: 2023 ( Subtotal = -$34,124 )
2023	2023	TUSKEGEE UNIVERSITY	1200 W MONTGOMERY RD	TUSKEGEE INSTITUTE	AL	36088	MACON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/9/2023	NON-COMPETING CONTINUATION	$376,373
2023	2021	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	5/15/2023	NEW	-$410,497
														Subtotal = -$34,124

Issue Date FY: 2022 ( Subtotal = $382,215 )
2022	2022	TUSKEGEE UNIVERSITY	1200 W MONTGOMERY RD	TUSKEGEE INSTITUTE	AL	36088	MACON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/1/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$382,215
2022	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/28/2022	NEW	$0
														Subtotal = $382,215

Issue Date FY: 2021 ( Subtotal = $410,497 )
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/16/2021	NEW	$410,497
														Subtotal = $410,497

Grand Total All Awards = $1,475,599

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Differences in Gastrointestinal Motility Between Males and Females in Health and Diabetes

Award Number: R01DK124269

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: 02/17/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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