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Comparative Analysis of Aneuploidy and Cellular Fragmentation Dynamics in Mammalian Embryos

Award Number: R01HD105320
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: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Comparative Analysis of Aneuploidy and Cellular Fragmentation Dynamics in Mammalian Embryos - PROJECT SUMMARY Whole chromosomal losses and gains (aneuploidy) that arise during meiosis and/or mitosis are major contributors to embryo loss and spontaneous miscarriage in natural and assisted reproduction, and their prevalence varies drastically in mammals across the Boreoeutheria tree. Although human, non-human primate, and bovine embryos all have a relatively high incidence of aneuploidy, murine embryos rarely exhibit aneuploidy, and equine and porcine embryos still await investigation with high-resolution, whole-genome methods. It is now well-established that meiotic and mitotic chromosome segregation errors are equally prevalent, but the specific contribution of mitotic aneuploidy to embryo loss amongst mammalian species is still unclear. Cellular fragmentation (CF), the dynamic process by which cytoplasmic bodies pinch off of embryos during cytokinesis, is often associated with aneuploidy and has been observed in both in vitro and in vivo-derived embryos from several mammals, albeit to varying degrees. While primate and equine embryos exhibit a high incidence of CF, porcine and bovine embryos show intermediate and a low frequency, respectively, and mouse embryos do not typically display CF. We recently demonstrated with human and rhesus macaque embryos, that CFs can enclose DNA that likely originated from the encapsulation of mis-segregated chromosomes into micronuclei during meiosis or mitosis. However, it remains unknown if chromosome sequestration via CF is an evolutionary shared process to correct embryo aneuploidy, or if there are species differences in CF dynamics. The overall goal of this proposal is to leverage the natural diversity in the aneuploidy and CF frequency across mammals and study the molecular mechanisms underlying micronucleation, aneuploidy, and CF using high-resolution sequencing approaches. For Aim 1, we will perform a combination of live-cell imaging, single-cell/CF DNA-sequencing, and copy number variation (CNV) analyses to establish the precise frequency of aneuploidy and chromosome encapsulation by CF in primate, equine, porcine, and bovine embryos. Aim 2 will focus on identifying differentially expressed genes between fragmented and non-fragmented embryos within and across the same mammals using RNA-sequencing. In Aim 3, we propose to manipulate the expression of previously discovered and/or newly identified differentially expressed CF-related genes in murine and bovine embryos. We will then assess the impact of gene knockdown or overexpression on preimplantation embryo development in vitro using real- time imaging and single-cell/CF CNV assessment. Implantation potential and subsequent embryogenesis will also be evaluated in vivo by transferring murine embryos with or without gene manipulation to pseudo-pregnant female recipient mice. Overall, the proposed study will greatly advance our understanding of the molecular mechanisms involved in chromosome mis-segregation during early mammalian embryogenesis, the findings from which can be applied to improving reproductive efficiency in agriculturally important species and human in vitro fertilization (IVF) success by reducing the incidence of embryo 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: 2026 ( Subtotal = $485,382 )
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	5	3/19/2026	NON-COMPETING CONTINUATION	$485,382
														Subtotal = $485,382

Issue Date FY: 2025 ( Subtotal = $485,426 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	4	4/9/2025	NON-COMPETING CONTINUATION	$485,426
														Subtotal = $485,426

Issue Date FY: 2024 ( Subtotal = $521,688 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	3	3/21/2024	NON-COMPETING CONTINUATION	$474,261
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	001	3	5/7/2024	NON-COMPETING CONTINUATION	$47,427
														Subtotal = $521,688

Issue Date FY: 2023 ( Subtotal = $525,935 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	2	3/13/2023	NON-COMPETING CONTINUATION	$525,935
														Subtotal = $525,935

Issue Date FY: 2022 ( Subtotal = $517,890 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	1	3/25/2022	NEW	$517,890
														Subtotal = $517,890

Grand Total All Awards = $2,536,321

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Comparative Analysis of Aneuploidy and Cellular Fragmentation Dynamics in Mammalian Embryos

Award Number: R01HD105320

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: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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