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Effect of neonatal and adult stress on pelvic pain disorders and comorbidity

Award Number: R01DK099611
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: 08/25/2014
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Effect of neonatal and adult stress on pelvic pain disorders and comorbidity - Project Summary Chronic pain and mood disorders are highly comorbid, particularly in patients with a history of early life stress (ELS) or trauma. In patients with Urologic Chronic Pelvic Pain Syndromes (UCPPS), the severity of ELS has been associated with a centralized pain phenotype with patients reporting greater widespread pain and negative mood, and reduced likelihood of symptom improvement. Neuroimaging studies revealed functional connectivity changes that may specifically predispose UCPPS patients with ELS to greater symptom burden and comorbidity. ELS has also been correlated with reductions in hippocampal gray matter volume and increased DNA methylation on stress-responsive genes, particularly in patients with major depressive disorder, a common comorbidity of UCPPS. The hippocampus negatively regulates the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response and is often altered in patients with centralized pain disorders. Voluntary exercise is an effective treatment for most mood and centralized pain disorders and significantly increases hippocampal neurogenesis and has been shown to impact epigenetic modifications. Our mouse model of ELS using neonatal maternal separation (NMS) demonstrates urogenital hypersensitivity, increased bladder output, widespread allodynia, impaired reward behaviors, and evidence of altered hippocampal regulation of the HPA axis. These outcomes can be exacerbated by acute exposure to water avoidance stress (WAS) in adulthood and attenuated by voluntary wheel running. Here we provide preliminary evidence of reduced hippocampal gray matter volume, DNA methylation, and blunted neurochemical signals following WAS, suggesting that reduced hippocampal integrity may be driving the NMS-related outcomes, similar to what has been observed in clinical populations. Our central hypothesis is that ELS-induced changes in the hippocampus can be modified by increasing physical activity, thereby attenuating urogenital and widespread hypersensitivity. We will test this hypothesis in two specific aims. Our first specific aim will determine whether increasing physical activity can prevent structural and neurochemical changes in the hippocampus and susceptibility to acute stress exposure in NMS mice. Our second specific aim will determine the impact of DNA methylation in the hippocampus on NMS-related outcomes and whether this process can be attenuated by increasing physical activity. At the completion of this project we will have gained novel and important information on the impact of ELS on hippocampal integrity, which we have identified as a potential integrator of centralized pain and comorbid mood disorders. Determining how increasing voluntary physical activity impacts ELS-related hippocampal and sensitivity changes will provide further evidence for the use of exercise as a powerful non-pharmacologic therapeutic intervention for treating UCPPS patients with a history of ELS and possibly preventing the development of symptoms in at-risk populations.


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 = $363,735 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	2/28/2024	NON-COMPETING CONTINUATION	$341,001
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	5/20/2024	NON-COMPETING CONTINUATION	$22,734
														Subtotal = $363,735

Issue Date FY: 2023 ( Subtotal = $398,277 )
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	2/22/2023	NON-COMPETING CONTINUATION	$398,277
														Subtotal = $398,277

Issue Date FY: 2022 ( Subtotal = $401,658 )
2022	2022	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	4/22/2022	NON-COMPETING CONTINUATION	$399,653
2022	2018	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	9/26/2022	NON-COMPETING CONTINUATION	$2,005
														Subtotal = $401,658

Issue Date FY: 2021 ( Subtotal = $404,214 )
2021	2021	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	3/18/2021	NON-COMPETING CONTINUATION	$404,214
2021	2020	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	6/8/2021	COMPETING CONTINUATION	$2,163
2021	2018	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	6/8/2021	NON-COMPETING CONTINUATION	-$2,163
														Subtotal = $404,214

Issue Date FY: 2020 ( Subtotal = $404,214 )
2020	2020	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	4/13/2020	COMPETING CONTINUATION	$404,214
														Subtotal = $404,214

Issue Date FY: 2018 ( Subtotal = $328,425 )
2018	2018	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/10/2018	NON-COMPETING CONTINUATION	$328,425
														Subtotal = $328,425

Issue Date FY: 2017 ( Subtotal = $328,425 )
2017	2017	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/26/2017	NON-COMPETING CONTINUATION	$32,843
2017	2017	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/6/2017	NON-COMPETING CONTINUATION	$295,582
														Subtotal = $328,425

Issue Date FY: 2016 ( Subtotal = $328,425 )
2016	2016	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/29/2016	NON-COMPETING CONTINUATION	$328,425
														Subtotal = $328,425

Issue Date FY: 2015 ( Subtotal = $328,425 )
2015	2015	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/22/2015	NON-COMPETING CONTINUATION	$328,425
														Subtotal = $328,425

Issue Date FY: 2014 ( Subtotal = $328,425 )
2014	2014	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE	3901 RAINBOW BOULEVARD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/25/2014	NEW	$328,425
														Subtotal = $328,425

Grand Total All Awards = $3,614,223

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Effect of neonatal and adult stress on pelvic pain disorders and comorbidity

Award Number: R01DK099611

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: 08/25/2014

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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