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In vivo role of RhoA in early pregnancy

Award Number: R03HD097384
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: 01/17/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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In vivo role of RhoA in early pregnancy - 7. Project Summary/Abstract: Early pregnancy loss is a major public health problem in reproductive women. The oviduct/fallo- pian tube and uterus play essential roles in supporting early pregnancy events, such as fertiliza- tion, preimplantation embryo development, embryo transport, and embryo implantation. RhoA is a prominent member of the Rho family of GTPases with crucial cellular functions. It is highly ex- pressed in the gestation day 3.5 (preimplantation) mouse oviduct and uterus, especially the api- cal side of uterine luminal epithelium that is the initial site of embryo-maternal interactions. Es- sential cell-type specific in vivo functions of RhoA in different systems are being revealed in mouse genetic models. The in vivo functions of RhoA in the female reproductive system are largely unknown. To investigate in vivo function of RhoA in the oviduct and uterus for supporting early pregnancy, we generated a RhoA conditional knockout mouse model (RhoAd/d) by cross- ing RhoAf/f mice with Pgr-Cre mice. Progesterone (P4) deficiency in RhoAd/d females led us to identify a novel role of RhoA in steroidogenesis in the corpus luteum. RhoAd/d females have nor- mal ovulation but implantation failure partially due to P4 deficiency. Exogenous P4 treatment could rescue embryo implantation but with significantly reduced number of implantation sites in RhoAd/d females, suggesting impaired early pregnancy in RhoAd/d females. Multiple early preg- nancy events occur in the oviduct and uterus. It is unknown which event(s) that RhoA plays a role in. Our long-term goal is to understand molecular mechanisms in regulating early preg- nancy. The defined objective of this R03 application is to identify the impaired early pregnancy event(s) leading to reduced implantation sites in P4-treated RhoAd/d females. Based on our pre- liminary data, we formulate the central hypothesis that RhoA in the oviduct and uterus supports early pregnancy. To achieve the goal of this application, we will pursue two specific aims: deter- mine spatiotemporal expression of RhoA in oviduct and uterus during early pregnancy (Aim 1) and test the hypothesis that RhoA in oviduct and uterus supports early pregnancy events (Aim 2). To overcome P4 deficiency in RhoAd/d mice and to generate the most suitable in vivo control for RhoAd/d mice, unilateral ovary transplantation will be performed in control (RhoAf/f) mice with a RhoAd/d ovary and in RhoAd/d mice with a control ovary. Unilateral ovary transplantation, realtime PCR, and immunohistochemistry are among the approaches that will be employed. The proposed work is significant because understanding functions of RhoA in early pregnancy will give novel insights into factors that affect early pregnancy thus provide information for develop- ing diagnostic and therapeutic approaches to detect and treat early pregnancy loss.


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: 2023 ( Subtotal = -$509 )
2023	2020	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Child Health and Human Development Extramural Research	000	2	5/10/2023	NON-COMPETING CONTINUATION	-$509
														Subtotal = -$509

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Child Health and Human Development Extramural Research	000	2	12/1/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $75,500 )
2020	2020	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Child Health and Human Development Extramural Research	000	2	12/18/2019	NON-COMPETING CONTINUATION	$67,950
2020	2020	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Child Health and Human Development Extramural Research	001	2	2/7/2020	NON-COMPETING CONTINUATION	$7,550
														Subtotal = $75,500

Issue Date FY: 2019 ( Subtotal = $75,250 )
2019	2019	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Child Health and Human Development Extramural Research	000	1	1/17/2019	NEW	$75,250
														Subtotal = $75,250

Grand Total All Awards = $150,241

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In vivo role of RhoA in early pregnancy

Award Number: R03HD097384

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: 01/17/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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