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Biological mechanisms that eliminate aneuploid cells from a mosaic conceptus in the mouse model system

Award Number: R01HD101489
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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Biological mechanisms that eliminate aneuploid cells from a mosaic conceptus in the mouse model system - Project Summary Many women struggle with infertility with only around 30% of pregnancies progressing to live birth and the remainder failing through spontaneous abortions, the majority of which are associated with aneuploidy. Here we use a mouse model for mosaic aneuploidy to study the effects of chromosome mosaicism on development of the conceptus through the pre-, peri-and early post-implantation stages. We have previously shown that aneuploidy results in two different responses in different adjacent tissues of the pre-implantation embryo: cell cycle delay in the extra-embryonic trophectoderm that will establish the placenta and apoptosis in the inner cell mass that will establish the foetus. We will now determine the fate of the majority of aneuploid cells that persist into implantation stages and how, in many cases, these can be eliminated without compromising implantation morphogenesis and the associated transition in the state of pluripotency. We will determine the extent to which the embryo can compensate for lost aneuploid cells to ensure development and determine the mechanisms employed by different post-implantation tissues to cope with aneuploidy and protect the pluripotent lineage that generates all germ layers and germline. As studies in diverse organisms indicate that global gene expression and translation levels correlate with the degree of aneuploidy, we will determine whether aneuploidy in the embryo results in proteomic imbalance leading to a common set of proteotoxic stress responses that induce autophagy. We will elucidate the role of autophagy in the elimination of aneuploid cells from the embryo and determine the roles of p53 and mTOR in this process. Our study will shed light onto competition between aneuploid and diploid cells in development and will uncover new pathways that regulate embryo growth and plasticity. It will inform IVF strategies in the clinic by building a working knowledge of circumstances in which human embryos diagnosed as mosaic should or should not be discarded. It will enable a more accurate assessment of the developmental potential of mosaic aneuploid embryos and permit the development of better methods to assess the probability of successful pregnancy.


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 = $466,959 )
2025	2025	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	5	1/15/2025	NON-COMPETING CONTINUATION	$466,959
														Subtotal = $466,959

Issue Date FY: 2024 ( Subtotal = $513,655 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	4	1/11/2024	NON-COMPETING CONTINUATION	$466,959
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	001	4	5/16/2024	NON-COMPETING CONTINUATION	$46,696
														Subtotal = $513,655

Issue Date FY: 2023 ( Subtotal = $518,843 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	3	2/4/2023	NON-COMPETING CONTINUATION	$518,843
														Subtotal = $518,843

Issue Date FY: 2022 ( Subtotal = $518,843 )
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	001	2	4/24/2022	NON-COMPETING CONTINUATION	$51,886
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	2	1/27/2022	NON-COMPETING CONTINUATION	$466,957
														Subtotal = $518,843

Issue Date FY: 2021 ( Subtotal = $518,843 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	1	3/29/2021	NEW	$515,745
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	001	1	3/31/2021	NEW	$3,098
														Subtotal = $518,843

Grand Total All Awards = $2,537,143

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Biological mechanisms that eliminate aneuploid cells from a mosaic conceptus in the mouse model system

Award Number: R01HD101489

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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