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Epigenetic barriers to trophoblast differentiation from pluripotent stem cells

Award Number: R01HD093783
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: 12/02/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2023

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Epigenetic barriers to trophoblast differentiation from pluripotent stem cells - PROJECT SUMMARY Murine trophoblast stem cells (TSCs) are cells isolated from blastocyst stage mouse embryos that are capable of differentiation into multiple trophoblast cell types in vitro and can colonize the placenta in utero. These cells have greatly advanced the study of trophoblast development, due to the ability to expand TSCs and differentiate them in vitro, facilitating cytological, biochemical, and epigenomic studies. However, no well-validated human TSCs have been described, limiting these studies to mouse models. One potential solution that has been pursued by multiple groups is the trans-differentiation of pluripotent stem cells (PSCs), which encompass both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), into trophoblast. Although PSCs can trans-differentiate into cells with many features of TSCs, these cells, called trophoblast stem-like cells (TS-LCs), do not have the developmental potential or self-renewal capacity of TSCs. Consequently, TS-LCs are limited as models for trophoblast function. These findings reveal there is an epigenetic block to trans-differentiation that must be overcome to produce bona fide induced trophoblast sem cells (iTSCs) from PSCs. We propose three Aims, two of which will characterize epigenetic features in PSCs that contribute to the trans-differentiation barrier. In the third Aim, we propose to use a combination of genome engineering and a novel hybrid differentiation/trans-differentiation protocol to overcome this barrier and produce bona fide iTSCs. Successful completion of these studies will provide considerable insight into the epigenetic barriers to trans-differentiation, and potentially the first bona fide iTSC lines derived from human PSCs.


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 = $0 )
2024	2022	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	000	5	12/5/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $319,200 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	001	5	4/20/2022	NON-COMPETING CONTINUATION	$31,921
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	000	5	11/17/2021	NON-COMPETING CONTINUATION	$287,279
														Subtotal = $319,200

Issue Date FY: 2021 ( Subtotal = $319,384 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	000	4	12/2/2020	NON-COMPETING CONTINUATION	$293,312
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	001	4	2/9/2021	NON-COMPETING CONTINUATION	$26,072
														Subtotal = $319,384

Issue Date FY: 2020 ( Subtotal = $326,088 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	001	3	2/12/2020	NON-COMPETING CONTINUATION	$32,609
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	000	3	11/8/2019	NON-COMPETING CONTINUATION	$293,479
														Subtotal = $326,088

Issue Date FY: 2019 ( Subtotal = $326,267 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	001	2	11/15/2018	NON-COMPETING CONTINUATION	$326,267
2019	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	000	1	11/14/2018	NEW	$0
														Subtotal = $326,267

Issue Date FY: 2018 ( Subtotal = $338,082 )
2018	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	000	1	12/2/2017	NEW	$338,082
														Subtotal = $338,082

Grand Total All Awards = $1,629,021

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Epigenetic barriers to trophoblast differentiation from pluripotent stem cells

Award Number: R01HD093783

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: 12/02/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2023

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