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Cellular and Molecular Mechanisms of Germline Regeneration

Award Number: R35GM138008
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: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Cellular and Molecular Mechanisms of Germline Regeneration - PROJECT SUMMARY Humans and well-established research organisms lack the ability to regenerate their reproductive cells (germ cells) and reproductive organs. Research findings from these organisms established the current view that germ cells are a distinct lineage separated from the soma; therefore, the loss of germ cells renders an organism infertile because new germ cells cannot be derived from the soma. Contradicting this widely accepted view is the fact that many organisms (e.g. hydra, flatworms, segmented worms, and sea stars) can readily regenerate germ cells. However, the cellular source of regenerated germ cells in these organisms is very poorly understood. The goal of my laboratory is to close this knowledge gap and define the cellular origins and molecular mechanisms of germ cell regeneration. Addressing this is not feasible using established research organisms like mice, fruit flies, and nematodes, because they do not regenerate germ cells. Furthermore, many of the organisms that can regenerate germ cells are not conducive to studying the mechanisms of this process because they lack transgenic tools, or their anatomies present technical challenges such as large and opaque bodies, or inaccessibility of reproductive organs. These limitations prevent the use of live imaging – a key tool to trace the lineages of germ cells and their source cells. We use a segmented worm, Platynereis dumerilii, for studying germ cell regeneration. Platynereis is well-suited for this study because germ cell regeneration can be induced and is achieved quickly; transcriptome databases, a draft genome, and transgenic tools (critical for genetic lineage tracing) are available; and a small and transparent body makes it excellent for live imaging. Therefore, Platynereis is a research organism that presents a rare opportunity to combine the modern techniques required to study germ cell regeneration (live-imaging, genetic lineage tracing, transcriptomics) in the relevant post-embryonic life stages (i.e. juveniles, adults) which are typically challenging to image live. We postulate three possible models for the cellular sources for the regenerated germ cells: 1) pluri/multipotent stem cells regenerate both somatic and germ cells; 2) a lineage-restricted cell population is dedicated to regenerating only the germ cells; or 3) somatic cells transdifferentiate into germ cells by reprogramming. Our experimental approach will be to: a) Test between the three cellular models of germ cell regeneration via genetic cell lineage tracing and live imaging. This will allow us to identify the exact cell lineages that give rise to germ cells during development and regeneration. b) Identify the molecular changes taking place during reprogramming source cells into germ cells by single cell RNA sequencing. This will allow us to obtain transcriptome trajectories over the course of regeneration and identify cell type-specific markers in the source cells, the intermediate states, and the new germ cells. These markers will be tested for function in future studies. The project will significantly contribute to our fundamental understanding of germ cell biology and the soma-germ cell distinction.


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: 2024 ( Subtotal = $387,960 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Biomedical Research and Research Training	000	6	5/21/2024	NON-COMPETING CONTINUATION	$387,960
														Subtotal = $387,960

Issue Date FY: 2023 ( Subtotal = $388,376 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	5	5/12/2023	NON-COMPETING CONTINUATION	$388,376
														Subtotal = $388,376

Issue Date FY: 2022 ( Subtotal = $380,372 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	003	4	5/23/2022	NON-COMPETING CONTINUATION	$392,997
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	006	3	7/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$116,227
2022	2021	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Biomedical Research and Research Training	000	2	2/11/2022	NON-COMPETING CONTINUATION	-$246,791
2022	2021	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Biomedical Research and Research Training	001	2	2/11/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	002	3	2/15/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$234,166
2022	2021	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Biomedical Research and Research Training	004	2	7/29/2022	NON-COMPETING CONTINUATION	-$66,227
2022	2021	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Biomedical Research and Research Training	005	2	7/29/2022	SUPPLEMENT FOR EXPANSION	-$50,000
														Subtotal = $380,372

Issue Date FY: 2021 ( Subtotal = $463,659 )
2021	2021	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Biomedical Research and Research Training	001	2	7/20/2021	SUPPLEMENT FOR EXPANSION	$50,000
2021	2021	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Biomedical Research and Research Training	000	2	5/25/2021	NON-COMPETING CONTINUATION	$413,659
														Subtotal = $463,659

Issue Date FY: 2020 ( Subtotal = $401,794 )
2020	2020	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Biomedical Research and Research Training	000	1	6/18/2020	NEW	$401,794
														Subtotal = $401,794

Grand Total All Awards = $2,022,161

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Cellular and Molecular Mechanisms of Germline Regeneration

Award Number: R35GM138008

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: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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