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Centromere Integrity and Cytoskeletal Function in Oocyte Aneuploidy and Reproductive Aging

Award Number: R01HD121559
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: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Centromere Integrity and Cytoskeletal Function in Oocyte Aneuploidy and Reproductive Aging - PROJECT SUMMARY Chromosome segregation errors in mammalian oocytes are a leading cause of infertility, miscarriage, and developmental conditions such as Down syndrome. These errors increase significantly with maternal age and highlight the unique vulnerabilities of the oocyte: prolonged arrest, acentrosomal spindle assembly, and epigenetically maintained chromatin. Although the loss of chromosome cohesion during advancing maternal age has long been considered an explanation, it occurs gradually with age and is unlikely to account for the near- exponential rise in aneuploidy observed at advanced reproductive ages. Our findings, alongside those of others, demonstrate that cytoskeletal disorganization alone is sufficient to trigger premature sister chromatid separation and that even young oocytes, which maintain robust cohesion, frequently exhibit segregation errors. This proposal focuses on the centromere as a dynamic regulatory hub that coordinates kinetochore assembly and spindle attachment, as well as on the spindle as a structural system that provides a buffer against centromere dysfunction. Our central hypothesis posits that meiotic fidelity relies on the integrity of the centromere- cytoskeleton axis and that its age-sensitive breakdown leads to chromosome segregation errors. Using mouse oocytes, we will integrate TRIM-Away-mediated protein depletion, synthetic oocyte aging platforms, and quantitative high-resolution live imaging assays to analyze how centromere proteins (e.g., CENP-A, CENP-C), centromeric DNA composition, and microtubule-associated proteins (MAPs) interact to protect chromosome segregation. Aim 1 will identify how CENP-A and downstream kinetochore components support kinetochore function and spindle assembly checkpoint signaling. Aim 2 will reveal how differences in centromeric DNA and the CENP-B–CENP-C axis contribute to chromosome-specific missegregation risk. Aim 3 will explore how MAPs maintain spindle structure and compensate for compromised centromeres in aging oocytes. These studies will demonstrate how centromeric weakening, chromatin asymmetries, and spindle disorganization collectively undermine meiotic fidelity in aged oocytes. This research reframes reproductive aging as a failure of an integrated chromatin–cytoskeletal system, highlighting new molecular targets to mitigate age-related fertility decline. By combining conceptual innovation with cutting-edge experimental tools in live oocytes, our approach presents a powerful strategy to uncover the molecular origins of aneuploidy and enhance opportunities for intervention in reproductive aging.


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 = $698,032 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	1	6/25/2026	NEW	$698,032
														Subtotal = $698,032

Grand Total All Awards = $698,032

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Centromere Integrity and Cytoskeletal Function in Oocyte Aneuploidy and Reproductive Aging

Award Number: R01HD121559

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: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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