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Characterization of the gene regulatory network governing the first cell fate decision in mammalian embryonic development

Award Number: R01HD104971
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Characterization of the gene regulatory network governing the first cell fate decision in mammalian embryonic development - PROJECT SUMMARY Although the “master regulators” that maintain the self-renewal of pluripotent embryonic stem cells and extraembryonic trophoblast stem cells are relatively well understood, little is known about how these transcription factors are regulated in vivo at early stages of embryogenesis. Molecular genetics and embryology studies have identified signaling pathways required to direct cells to become trophoblast or embryonic epiblast, but the transcription factors that activate expression of pluripotency master regulators (PMRs) or trophoblast master regulators (TMRs) in each cell remain largely unknown. This major gap in our understanding of early development is due to at least two factors. First, technical barriers prevent the use of many molecular and genomics approaches in embryos consisting of low cell numbers. Second, there are significant discrepancies between the totipotent blastomeres of early embryos (where most PMRs and TMRs begin to be expressed) and cell culture models of totipotent cells. Therefore, a new approach that combines comprehensive methods for identification of regulators of PMR and TMR expression with sensitive new methods of testing their functions in vivo is necessary to fill this major gap in our understanding of the early embryonic gene regulatory network (GRN). We propose three aims to address this problem. Aim 1 is focused on comprehensive identification of transcription factors regulating PMRs and TMRs and uncovering their regulatory functions. Aim 2 will generate a lineage-resolved atlas of epigenetic changes that occur as cells select either the epiblast or trophoblast fate, as well as identify the direct targets of transcription factors that participate in cell fate specification. In Aim 3, we propose to dissect the mechanisms by which developmental transcription factors help elicit these epigenetic changes and generate a model of the totipotent GRN that mediates this decision. Successful completion of these studies will reshape our understanding of early embryonic gene regulation, as well as specification of epiblast and trophoblast cell fate.


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 = $515,898 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	000	4	4/8/2025	NON-COMPETING CONTINUATION	$515,898
														Subtotal = $515,898

Issue Date FY: 2024 ( Subtotal = $510,739 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	000	3	3/14/2024	NON-COMPETING CONTINUATION	$464,308
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	001	3	5/6/2024	NON-COMPETING CONTINUATION	$46,431
														Subtotal = $510,739

Issue Date FY: 2023 ( Subtotal = $515,898 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	000	2	3/8/2023	NON-COMPETING CONTINUATION	$515,898
														Subtotal = $515,898

Issue Date FY: 2022 ( Subtotal = $549,648 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Child Health and Human Development Extramural Research	000	1	7/12/2022	NEW	$549,648
														Subtotal = $549,648

Grand Total All Awards = $2,092,183

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Characterization of the gene regulatory network governing the first cell fate decision in mammalian embryonic development

Award Number: R01HD104971

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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