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Quantifying germ cell lineage dynamics in mammalian oogenesis

Award Number: F30HD117592
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Quantifying germ cell lineage dynamics in mammalian oogenesis - PROJECT SUMMARY/ABSTRACT Infertility affects 10% of people with ovaries between the ages of 15-44 in the United States, and reduced oocyte number in the ovarian reserve is a leading factor underlying reduced fertility in cases of premature ovarian insufficiency and age-related fertility decline. In mammals, including humans, many oocyte precursors (oogonia) are initially generated in the developing ovary, but the vast majority are culled before or shortly after birth through the process of fetal oocyte attrition (FOA). This yields a much smaller pool of primordial follicles responsible for maintaining ovarian fertility throughout reproductive life: the ovarian reserve. While migrating through the early embryo, early germ cells accrue cellular heterogeneity which manifests as variable genomic demethylation and epigenetic reprogramming, DNA damage and genotoxicity, meiotic entry timing, and exposure and response to signaling cues. This heterogeneity and the massive reduction in oocyte population during FOA have led many to speculate that FOA functions as a selective quality control filter for only the highest quality oocytes to enter the ovarian reserve. However, whether developing germ cell lineages are actively selected to survive based on earlier cellular heterogeneity remains unknown. I propose to quantify lineage dynamics during mammalian oogenesis to characterize germ cell selection and determine the functional importance of early germ cell heterogeneity for shaping the developing ovarian reserve. I hypothesize that heterogeneous early germ cells undergo non-neutral clonal selection during FOA to generate an oocyte pool with shared transcriptomic and chromatin accessibility features. Leveraging in vivo single-cell inducible lineage tracing with genetic barcodes, single-cell multi-omics profiling, and repeat clonal sampling throughout in vitro oocyte differentiation, this proposal will 1) characterize the nature of germ cell selection during FOA through clone size distribution analysis, 2) profile the extent of transcriptomic and epigenomic heterogeneity in the germline before and selection, 3) identify cell states of early germ cells that predict and actively drive successful oocyte differentiation and survival. This approach will identify essential mechanisms for oocyte development and survival that can be applied to improve human in vitro oogenesis protocols and inform the selection of high-quality oocytes for use in clinical assisted reproductive technologies. I have developed a rigorous training plan with my mentors Dr. Diana Laird (sponsor) and Dr. Dan Wagner (co-sponsor) to empower my continued development as a scientist and clinician. With Dr. Laird’s expertise in germ cell development, mouse genetics, and quantitative imaging, Dr. Wagner’s knowledge of single-cell lineage tracing with molecular recorders, cell fate specification, and bioinformatics analyses, and consultation from Drs. Nowakowski, Avagyan, and Bowling, I am well equipped to develop the interdisciplinary skillset needed to execute this project. The support provided by this F30 NRSA predoctoral fellowship award will ensure that I receive the training and mentorship needed to complete the proposed research.


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 = $43,152 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Child Health and Human Development Extramural Research	000	2	12/4/2025	NON-COMPETING CONTINUATION	$42,576
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Child Health and Human Development Extramural Research	001	2	4/3/2026	NON-COMPETING CONTINUATION	$576
														Subtotal = $43,152

Issue Date FY: 2025 ( Subtotal = $42,314 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Child Health and Human Development Extramural Research	001	1	11/27/2024	NEW	$0
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Child Health and Human Development Extramural Research	000	1	11/27/2024	NEW	$41,750
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Child Health and Human Development Extramural Research	002	1	6/23/2025	NEW	$564
														Subtotal = $42,314

Grand Total All Awards = $85,466

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Quantifying germ cell lineage dynamics in mammalian oogenesis

Award Number: F30HD117592

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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