Thursday, July 3, 2025 7/3/2025

Molecular signaling in uterine receptivity to implantation

Award Number: R01HD068524
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: 09/26/2011
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Molecular signaling in uterine receptivity to implantation - Embryo implantation is a gateway to pregnancy success. A crosstalk between the blastocyst and uterus is vital to implantation. Formation of a healthy implantation chamber (crypt) is critical for normal embryo implantation; an abnormal crypt results in subfertility. Planar cell polarity (PCP) is a classic downstream target of the non-canonical Wnt5a signaling pathway. Uterine deletion of Vang- like protein 2 (Vangl2), a major PCP component, severely derails crypt formation, embryo spacing, and decidualization, ultimately compromising pregnancy outcomes. We have found that crypts invariably originate with preexisting glands conferring direct communication between the implanting blastocyst and glands. Heparin-binding EGF-like growth factor (HB-EGF) is exclusively expressed in the crypt epithelium surrounding the blastocyst, and beads preloaded with HB-EGF, if transferred to day 4 pseudopregnant uteri, evoke implantation-like changes similar to normal pregnancy. However, these responses fail to occur in uteri missing Vangl2, suggesting an intersection of Vangl2 with HB-EGF signaling. HB-EGF executes its function via the EGF family of receptors (Erbbs 1-4) as homodimers or heterodimers and induces tyrosine phosphorylation. This proposal will test a novel hypothesis that HB-EGF signaling intersects with PCP signaling by engaging the ErbBs in implantation. HB-EGF working via ErbBs 1-4 induces tyrosine phosphorylation. Our preliminary results show a physical association of Vangl2 with ErbB2 and ErbB3, suggesting that these receptors, if activated by HB-EGF, transphosphorylate Vangl2. The following two specific aims will study interactions between PCP and HB-EGF signaling in implantation using mouse models: Specific aim 1 will test the hypothesis that HB-EGF signaling intersects with Vangl2 signaling to direct the formation of an appropriate glands-crypt assembly for direct cross-talk between the implanting blastocyst and the glands. This interlocking of two different signaling pathways involves phosphorylation of members of the ErbB family of receptors followed by transphosphorylation of Vangl2. Specific aim 2 will test the hypothesis that the functional coupling of HB-EGF and Vangl2 signaling in implantation requires the presence of ErbB1, ErbB2 and/or ErbB3 in the uterine epithelium and/or stroma. We will use conditional deletion of ErbB1, ErbB2 and/or ErbB3 using Pgr-Cre and Ltf- iCre drivers to explore the Vangl2 phosphorylation status in the uterus, and correlate these results with pregnancy phenotypes. Successful completion of this project will reveal a conceptual attribute to the field of implantation and pregnancy biology that a growth factor signaling pathway intersects with PCP signaling in forming implantation chambers (crypts) for pregnancy success.


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 = $439,064 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	000	13	3/11/2025	NON-COMPETING CONTINUATION	$395,158
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	001	13	4/24/2025	NON-COMPETING CONTINUATION	$43,906
														Subtotal = $439,064

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	001	12	3/13/2024	NON-COMPETING CONTINUATION	$0
2024	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	000	12	12/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $439,064 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	000	12	2/16/2023	NON-COMPETING CONTINUATION	$439,064
2023	2022	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	002	11	4/18/2023	COMPETING CONTINUATION	$242,437
2023	2020	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	001	10	4/18/2023	NON-COMPETING CONTINUATION	-$242,437
														Subtotal = $439,064

Issue Date FY: 2022 ( Subtotal = $439,064 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	001	11	5/31/2022	COMPETING CONTINUATION	$439,064
2022	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	000	10	5/31/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $439,064

Issue Date FY: 2020 ( Subtotal = $381,333 )
2020	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	000	10	6/17/2020	NON-COMPETING CONTINUATION	$381,333
														Subtotal = $381,333

Issue Date FY: 2019 ( Subtotal = $387,807 )
2019	2019	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	001	9	8/21/2019	NON-COMPETING CONTINUATION	$0
2019	2019	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	000	9	7/8/2019	NON-COMPETING CONTINUATION	$387,807
														Subtotal = $387,807

Issue Date FY: 2018 ( Subtotal = $397,368 )
2018	2018	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	000	8	7/3/2018	NON-COMPETING CONTINUATION	$397,368
														Subtotal = $397,368

Issue Date FY: 2017 ( Subtotal = $397,368 )
2017	2017	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	002	7	6/19/2017	NON-COMPETING CONTINUATION	$397,368
2017	2016	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	001	6	11/29/2016	COMPETING CONTINUATION	$226,767
2017	2015	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	000	5	11/29/2016	NON-COMPETING CONTINUATION	-$226,767
														Subtotal = $397,368

Issue Date FY: 2016 ( Subtotal = $397,368 )
2016	2016	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	001	6	9/11/2016	COMPETING CONTINUATION	$397,368
2016	2015	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	452293039	HAMILTON	USA	Child Health and Human Development Extramural Research	000	5	9/8/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $397,368

Issue Date FY: 2015 ( Subtotal = $316,996 )
2015	2015	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	000	5	5/18/2015	NON-COMPETING CONTINUATION	$316,996
														Subtotal = $316,996

Issue Date FY: 2014 ( Subtotal = $316,022 )
2014	2014	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	000	4	6/20/2014	NON-COMPETING CONTINUATION	$316,022
														Subtotal = $316,022

Issue Date FY: 2013 ( Subtotal = $308,544 )
2013	2013	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	000	3	6/27/2013	NON-COMPETING CONTINUATION	$308,544
														Subtotal = $308,544

Issue Date FY: 2012 ( Subtotal = $325,125 )
2012	2012	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	000	2	6/18/2012	NON-COMPETING CONTINUATION	$325,125
														Subtotal = $325,125

Issue Date FY: 2011 ( Subtotal = $325,125 )
2011	2011	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Child Health and Human Development Extramural Research	000	1	9/26/2011	NEW	$325,125
														Subtotal = $325,125

Grand Total All Awards = $4,870,248

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Molecular signaling in uterine receptivity to implantation

Award Number: R01HD068524

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: 09/26/2011

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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