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Regulation of proliferation and differentiation in the male germ line adult stem cell lineage

Award Number: R35GM136433
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Regulation of proliferation and differentiation in the male germ line adult stem cell lineage - Project Summary / Abstract Our research is aimed at understanding the molecular mechanisms that regulate proliferation and differentiation in adult stem cell lineages. These events are of crucial importance for both short and long term health, as adult stem cell lineages underlie continued replacement of high turn over cell types in blood, skin, and the epithelial lining of the gut, as well as maintenance and repair of many other tissues in the body. Our primary focus is on elucidating the molecular circuitry that regulates the switch from precursor cell proliferation of onset of lineage appropriate differentiation. Failure to cleanly switch from proliferation to differentiation may underlie genesis of cancer in stem cell lineages, while failure to establish cell type specific gene expression for the proper differentiation program may lead to dysgenesis, scarring, fibrosis, or tissue degeneration. We utilize spermatogenesis in Drosophila as a model adult stem cell lineage in which the switch from proliferation to differentiation is especially amenable to study in vivo using an integrated combination of powerful genetic, genomic, cytological and biochemical tools. During spermatogenesis, mitotically proliferating spermatogonia switch to onset of meiotic prophase, during which spermatocytes express hundreds of novel transcripts required to regulate and mediate the dramatic changes in cell behavior and morphogenesis that eventually produce mature sperm. Our goal under the MIRA is an integrated, systems level understanding of how the different molecular mechanisms we have uncovered act in a pathway to trigger a clean switch from precursor cell proliferation, establish a stable program of cell type-specific gene expression, and regulate its execution to time and drive key steps in differentiation. Our approach will build upon recent technical advances and new discoveries made in the current funding period. Springing from our discovery that the key role of the RNA binding protein Bam required to trigger the switch from mitosis to meiosis is to repress expression of the nuclear RNA binding protein How, we will identify RNAs bound by How by immunoprecipitation, score for alternative splicing events that change immediately after How protein disappears from spermatogonia, and assess function of candidate How targets in vivo, for example, whether they modulate expression of cell cycle regulators or bind to promoters of differentiation genes as potential transcriptional regulators. Based on our finding that cell type specific isoforms of RNA binding proteins expressed in the first wave of spermatocyte transcription modulate alternative splicing, stability or translation of selected mRNAs expressed in the second wave, we will investigate how early onset RNA binding proteins regulate timing and execution of the meiotic cell cycle and cell type specific post meiotic cellular differentiation. Exploiting our genome wide, stage specific transcriptomic analysis, we will work upstream from the earliest promoters that turn on in young spermatocytes to explore potential transcription factors, chromatin regulators and nuclear architecture that may link onset of the gene expression program for terminal differentiation with action of How to stop mitotic proliferation and trigger onset of the meiotic program.


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 = $858,451 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	7	5/12/2026	NON-COMPETING CONTINUATION	$858,451
														Subtotal = $858,451

Issue Date FY: 2025 ( Subtotal = $904,601 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	6	7/23/2025	COMPETING CONTINUATION	$904,601
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	5	11/6/2024	NON-COMPETING CONTINUATION	$0
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	002	5	8/27/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $904,601

Issue Date FY: 2024 ( Subtotal = $851,548 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	5	5/21/2024	NON-COMPETING CONTINUATION	$851,548
														Subtotal = $851,548

Issue Date FY: 2023 ( Subtotal = $851,548 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	4	5/30/2023	NON-COMPETING CONTINUATION	$851,548
														Subtotal = $851,548

Issue Date FY: 2022 ( Subtotal = $865,643 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	5/26/2022	NON-COMPETING CONTINUATION	$851,548
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	3	9/9/2022	SUPPLEMENT FOR EXPANSION	$14,095
														Subtotal = $865,643

Issue Date FY: 2021 ( Subtotal = $875,806 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	2	8/24/2021	SUPPLEMENT FOR EXPANSION	$24,258
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	6/3/2021	NON-COMPETING CONTINUATION	$851,548
														Subtotal = $875,806

Issue Date FY: 2020 ( Subtotal = $672,827 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	1	8/12/2020	SUPPLEMENT FOR EXPANSION	$31,071
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	5/7/2020	NEW	$641,756
														Subtotal = $672,827

Grand Total All Awards = $5,880,424

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Regulation of proliferation and differentiation in the male germ line adult stem cell lineage

Award Number: R35GM136433

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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