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Regulation of Uterine Smooth Muscle Excitability

Award Number: R01HD037831
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/1999
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Regulation of Uterine Smooth Muscle Excitability - A successful pregnancy and delivery require two distinct states of uterine activity: a quiescent state characterized by weak, asynchronous, regional contractions throughout pregnancy; and an activated state in which contractions increase in force, frequency, and synchrony to expel the fetus at term. These states are controlled by electrical activity of the uterine (myometrial) smooth muscle cells (MSMCs). Two key ions regulate MSMC electrical activity: calcium (Ca2+), which enters the cell, depolarizes the membrane, and activates the contractile machinery; and potassium (K+), which effluxes from the cell, repolarizes (inside of the membrane more negative than outside) the membrane, and returns the cell to the resting state. The traditional model is that Ca2+ enters through voltage-gated Ca2+ (Cav) channels and activates the large-conductance Ca2+-activated K+ channel KCa1.1. Here, we propose that whereas this model explains the basal, quiescent state, it is insufficient to explain the activated, inflammatory state characteristic of term labor. Instead, we propose a new model in which low KCa1.1 activity and Cav-mediated Ca2+ influx maintain MSMC membrane polarization in basal states, but high KCa1.1 activity and Ca2+ influx through store-operated Ca2+ (SOC) channels are required for membrane repolarization in inflammatory states. This new model is founded on several pieces of published and preliminary data. First, KCa1.1 is substantially more active in MSMCs isolated from laboring women than in those from non-laboring women. Second, when the inflammatory protein alpha-2- macroglobulin (α2M) binds to its receptor, low density lipoprotein receptor-related protein 1 (LRP1), KCa1.1 activity enhances Ca2+ oscillations in MSMCs. Third, these Ca2+ oscillations are not inhibited by the Cav blocker nifedipine, but by SOC inhibitors. Finally, in MSMCs, KCa1.1 interacts with 21, the subunit that traffics Cav to the plasma membrane. To test our model, we will pursue three specific aims: 1) Determine the extent to which KCa1.1 is required for MSMC excitability in basal and inflammatory states; 2) Define the mechanism by which inflammatory stimuli enhance KCa1.1 and Ca2+ channel activity; and 3) Determine the mechanism by which KCa1.1 inhibits Cav-mediated Ca2+ influx. Insights gained from this work may lead to new therapeutic strategies to modulate uterine excitability and prevent aberrant uterine activity.


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: 2026 ( Subtotal = $0 )
2026	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	000	21	2/26/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	000	21	10/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $457,428 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	000	21	7/11/2023	NON-COMPETING CONTINUATION	$457,428
														Subtotal = $457,428

Issue Date FY: 2022 ( Subtotal = $463,357 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	000	20	8/3/2022	NON-COMPETING CONTINUATION	$463,357
														Subtotal = $463,357

Issue Date FY: 2021 ( Subtotal = $462,755 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	000	19	7/15/2021	NON-COMPETING CONTINUATION	$462,755
														Subtotal = $462,755

Issue Date FY: 2020 ( Subtotal = $463,146 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	003	18	7/2/2020	NON-COMPETING CONTINUATION	$463,146
2020	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	002	17	2/7/2020	COMPETING CONTINUATION	$0
2020	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	001	17	1/28/2020	COMPETING CONTINUATION	$0
2020	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	000	16	1/28/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $463,146

Issue Date FY: 2019 ( Subtotal = $475,096 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	001	17	9/25/2019	COMPETING CONTINUATION	$475,096
2019	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	000	16	9/25/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $475,096

Issue Date FY: 2018 ( Subtotal = $350,187 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	001	16	5/1/2018	NON-COMPETING CONTINUATION	$35,020
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	000	16	1/19/2018	NON-COMPETING CONTINUATION	$315,167
														Subtotal = $350,187

Issue Date FY: 2017 ( Subtotal = $350,187 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	001	15	6/21/2017	NON-COMPETING CONTINUATION	$35,020
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Child Health and Human Development Extramural Research	000	15	1/19/2017	NON-COMPETING CONTINUATION	$315,167
														Subtotal = $350,187

Issue Date FY: 2016 ( Subtotal = $346,684 )
2016	2016	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Child Health and Human Development Extramural Research	000	14	1/29/2016	NON-COMPETING CONTINUATION	$346,684
														Subtotal = $346,684

Issue Date FY: 2015 ( Subtotal = $341,433 )
2015	2015	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Child Health and Human Development Extramural Research	000	13	2/4/2015	NON-COMPETING CONTINUATION	$341,433
														Subtotal = $341,433

Issue Date FY: 2014 ( Subtotal = $366,787 )
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Child Health and Human Development Extramural Research	000	12	2/18/2014	COMPETING CONTINUATION	$366,787
														Subtotal = $366,787

Issue Date FY: 2010 ( Subtotal = $446,941 )
2010	2010	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Trans-NIH Recovery Act Research Support	000	11	8/19/2010	NON-COMPETING CONTINUATION	$446,941
														Subtotal = $446,941

Issue Date FY: 2009 ( Subtotal = $477,877 )
2009	2009	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Trans-NIH Recovery Act Research Support	001	10	8/28/2009	COMPETING CONTINUATION	$477,877
2009	2008	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Child Health and Human Development Extramural Research	000	9	8/28/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $477,877

Issue Date FY: 2008 ( Subtotal = $308,384 )
2008	2008	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Child Health and Human Development Extramural Research	000	9	2/12/2008	NON-COMPETING CONTINUATION	$308,384
														Subtotal = $308,384

Issue Date FY: 2007 ( Subtotal = $314,678 )
2007	2007	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Child Health and Human Development Extramural Research	000	8	1/16/2007	NON-COMPETING CONTINUATION	$314,678
														Subtotal = $314,678

Issue Date FY: 2006 ( Subtotal = $324,076 )
2006	2006	UNIVERSITY OF IOWA	ROOM B5K, JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Child Health and Human Development Extramural Research	000	7	3/3/2006	NON-COMPETING CONTINUATION	$324,076
														Subtotal = $324,076

Issue Date FY: 2005 ( Subtotal = $331,875 )
2005	2005	UNIVERSITY OF IOWA	ROOM B5K, JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Child Health and Human Development Extramural Research	000	6	1/1/2005	COMPETING CONTINUATION	$331,875
														Subtotal = $331,875

Issue Date FY: 2003 ( Subtotal = $165,770 )
2003	2003	UNIVERSITY OF IOWA	ROOM B5K, JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Child Health and Human Development Extramural Research	000	5		NON-COMPETING CONTINUATION	$165,770
														Subtotal = $165,770

Issue Date FY: 2002 ( Subtotal = $174,445 )
2002	2002	UNIVERSITY OF IOWA	ROOM B5K, JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Child Health and Human Development Extramural Research	000	4	6/21/2002	NON-COMPETING CONTINUATION	$160,939
2002	2002	UNIVERSITY OF IOWA	ROOM B5K, JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Child Health and Human Development Extramural Research	001	4	7/2/2002	SUPPLEMENT FOR EXPANSION	$13,506
														Subtotal = $174,445

Issue Date FY: 2001 ( Subtotal = $169,034 ) (Continued on the next page)
2001	2001	UNIVERSITY OF IOWA	ROOM B5K, JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Child Health and Human Development Extramural Research	000	3	6/7/2001	NON-COMPETING CONTINUATION	$156,254
Grand Total All Awards = $7,134,979

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Regulation of Uterine Smooth Muscle Excitability

Award Number: R01HD037831

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/1999

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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