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Regulation of mechanosensitive K+ channels in detrusor smooth muscle by estrogen

Award Number: R01DK119491
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: 09/19/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Regulation of mechanosensitive K+ channels in detrusor smooth muscle by estrogen - Project Summary The bladder must refrain from premature contraction during filling. This project investigates an intrinsic mechanism of detrusor muscles in mouse and humans that senses volume changes through the elongation of smooth muscle fibers. The mechanism is due to the expression and function of stretch-dependent K+ channels. Previous studies have shown that stretch of detrusor smooth muscle cells (SMCs) activates outward current that stabilizes the excitability of these cells. Blockers of the stretch-activated K+ channels cause significant activation of transient contractions (TCs) in the bladder wall during filling, and TCs are a primary stimulant of sensory information conveyed by pelvic afferents. We found that Kcnk2, which encodes the dominant stretch-dependent conductance TREK1 in detrusor SMCs, is down-regulated after loss of female hormones following ovariectomy. We noted a concomitant increase in TCs when TREK1 levels decreased. We also found that estrogen can rescue nearly normal bladder function after ovariectomy. Such findings do not completely agree with the literature regarding the effects of hormone replacement therapy on overactive bladder, and we will explore possible reasons for this discrepancy. One explanation could be that the timing of estrogen replacement could be critical for efficacy. Thus, we have proposed experiments to study the effects of the delay between ovariectomy and estrogen replacement on the ability of estrogen to restore Kcnk2 and TREK1 expression and normal bladder responses to filling. We have also found in preliminary experiments that there is a time- dependent loss of estrogen receptor α (ERα) after ovariectomy. Thus, we will investigate the time-dependence of the loss of estrogen receptors and the correlation between receptor loss and reduction in the effectiveness of estrogen replacement. Another idea to be investigated is that the balance between ERα and ERβ might change after ovariectomy, causing not only loss of effectiveness of estrogen replacement but also shifting the responses to estrogen from helpful to eleterious to normal bladder function. This question will be explored using animals with SMC-specific knockouts of ERα and ERβ. The project will use several state-of-the-art molecular and physiological assays to provide rigorous associations between expression of TREK1 and possibly TREK2 channels and bladder function. The consequences of changes in ERα and ERβ expression and estrogen regulation of Kcnk2 and Kcnk10 will provide new information about the role of stretch-dependent K+ conductances in bladder function and suggest a mechanism for the development of overactive bladder after menopause.


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 = $0 )
2025	2022	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $421,040 )
2022	2022	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/27/2022	NON-COMPETING CONTINUATION	$421,040
														Subtotal = $421,040

Issue Date FY: 2021 ( Subtotal = $421,040 )
2021	2021	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/27/2021	NON-COMPETING CONTINUATION	$421,040
														Subtotal = $421,040

Issue Date FY: 2020 ( Subtotal = $421,040 )
2020	2020	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/27/2020	NON-COMPETING CONTINUATION	$421,040
														Subtotal = $421,040

Issue Date FY: 2019 ( Subtotal = $421,040 )
2019	2019	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/7/2019	NON-COMPETING CONTINUATION	$421,040
														Subtotal = $421,040

Issue Date FY: 2018 ( Subtotal = $421,040 )
2018	2018	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/18/2018	NEW	$421,040
														Subtotal = $421,040

Grand Total All Awards = $2,105,200

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Regulation of mechanosensitive K+ channels in detrusor smooth muscle by estrogen

Award Number: R01DK119491

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: 09/19/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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