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Psychosocial Stress Effects on Regenerative Medicine Therapies for Lower Urinary Tract Disorders in Nonhuman Primates

Award Number: R01DK124639
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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This proposal is a response to PAS-19-241, Stimulating Urology Interdisciplinary Team Opportunity Research, the aim of which is to promote innovative, high-quality, interdisciplinary research relevant to the NIDDK. Importantly, this PAS and a prior workshop identified psychosocial factors in women with urinary incontinence as an important knowledge gap. To this end, we bring together experts from behavioral sciences, urology, molecular pathology, and regenerative medicine to explore further our initial findings that socially subordinate female monkeys do not respond as well to cell therapy for urinary incontinence as their dominant counterparts. We now propose a more comprehensive approach to assess (a) sympathetic nervous system (SNS) arousal, hypothalamic-pituitary-adrenal (HPA) activation, and impaired ovarian function in socially housed monkeys; and (b) the likely pathways by which social subordination stress affects structural and functional regeneration within the urinary sphincter. Two likely pathways through which social subordination stress may modulate these processes are cortisol and SNS effects on tissue and cell damaging inflammation and estrogen-deficiency-associated inhibition of cell mobilization. These processes are not mutually exclusive and may involve the CXCL12/CXCR4 signaling pathway. Based on our previous studies and the published literature, our central hypothesis is that psychosocial stress inhibits the regenerative effects of cell therapy by reducing the mobilization of tissue healing bone marrow progenitor cells, and increasing the presence of hematopoietic tissue damaging inflammatory cells in the urinary sphincter. This hypothesis will be tested in a prospective, randomized, nonhuman primate preclinical trial using our well-characterized female cynomolgus monkey model of psychosocial stress due to social subordination, and our model of intrinsic urinary sphincter deficiency. Our Specific Aims are to determine the effect of social status on: 1) the structural (cellular, acellular, vascular, innervation) and functional (urinary sphincter and bladder) effects of autologous skMPC therapy in female primates with ISD; 2) The injected lenti-M-cherry+ skMPC cell retention in, and lenti GFP+ labeled bone marrow cell mobilization to, the urinary sphincter of dominant and subordinate monkeys; 3) The effect of social subordination stress on abundance and polarization of inflammatory cells and associated molecules in the urinary sphincter; and 4) Whether social status effects on cell therapy-induced tissue regeneration are mediated by behavioral stress, SNS, HPA, or ovarian function. The results of this translational research will promote understanding of limitations and potential future regenerative medicine strategies for women with urinary incontinence.


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 = $631,695 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/11/2024	NON-COMPETING CONTINUATION	$631,695
														Subtotal = $631,695

Issue Date FY: 2023 ( Subtotal = $652,107 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	9/7/2023	NON-COMPETING CONTINUATION	$0
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/4/2023	NON-COMPETING CONTINUATION	$652,107
														Subtotal = $652,107

Issue Date FY: 2022 ( Subtotal = $676,122 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/1/2022	NON-COMPETING CONTINUATION	$676,122
														Subtotal = $676,122

Issue Date FY: 2021 ( Subtotal = $670,317 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/19/2021	NON-COMPETING CONTINUATION	$670,317
2021	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	7/14/2021	NEW	$0
														Subtotal = $670,317

Issue Date FY: 2020 ( Subtotal = $681,998 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/26/2020	NEW	$681,998
														Subtotal = $681,998

Grand Total All Awards = $3,312,239

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Psychosocial Stress Effects on Regenerative Medicine Therapies for Lower Urinary Tract Disorders in Nonhuman Primates

Award Number: R01DK124639

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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