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An analysis of the regulation and functions of a novel family of membraneless organelles in eukaryotic cells

Award Number: R01GM128440
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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An analysis of the regulation and functions of a novel family of membraneless organelles in eukaryotic cells - The eukaryotic cell is a highly compartmentalized structure that is subdivided into distinct functional areas by the presence of both membrane-bound and membraneless organelles. These latter compartments have also been referred to as biomolecular condensates. Although most of these membraneless structures have been identified only recently, condensate formation has been found to be important for many essential processes in the cell. It is therefore critical that we develop a thorough understanding of the mechanisms underlying condensate formation and the nature of their biological activities in the cell. We have been addressing these broader issues by studying the biology of one particular condensate, the Processing body, or P-body. This cytoplasmic granule is highly conserved and contains translationally- repressed mRNAs and proteins involved in the processing of these transcripts. Our efforts over the past 15 years have been focused on developing a better understanding of the physiological roles of these granules in the eukaryotic cell. Studies during the prior grant period furthered this understanding by identifying a potential role for P-bodies in the regulation of microtubule dynamics. Specifically, we found that a distinct subtype of P-body granule was induced when the integrity of the microtubule network was disrupted. Moreover, our preliminary data suggest that these granules may be involved in the specific turnover of the TUB mRNAs that encode tubulin monomers. The experiments in this proposal are organized into two aims that will (1) define the assembly pathway for these novel granules and (2) determine how their biological activities are regulated. The studies in Aim 1 will specifically test a model proposing that these novel granules form as a result of select P-body components being recruited to the TUB mRNAs. Interestingly, we have found that this latter decay in S. cerevisiae exhibits the hallmarks of tubulin autoregulation, a process that has been studied for decades in mammals. However, the decay machinery responsible for this mRNA turnover has not yet been identified. Therefore, the studies here could provide resolution for a long-standing question in tubulin biology. In Aim 2, we will examine how the biological activity of a biomolecular condensate can be controlled by specific constituents of that structure. We will specifically address a key question concerning the role of P-bodies with respect to mRNA stability. The primary issue is whether P-bodies are sites of decay or long-term storage for the resident mRNAs. The experiments here will test a model proposing that P-bodies can alternate between these different activities and that the transition from one state to the other is controlled by protein constituents of the granule, like the Hrr25 protein kinase. Finally, we will assess the possibility that the P-body decay machinery is portable and recruited to select messages that are targeted for degradation. In all, the completion of this work should provide us with a better understanding of the diversity and physiological roles of a conserved biomolecular condensate in eukaryotic cells.


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: 2025 ( Subtotal = $332,561 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	7	4/4/2025	NON-COMPETING CONTINUATION	$332,561
														Subtotal = $332,561

Issue Date FY: 2024 ( Subtotal = $332,561 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	002	6	5/23/2024	NON-COMPETING CONTINUATION	$332,561
2024	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	001	5	5/22/2024	COMPETING CONTINUATION	$5,074
2024	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	4	5/22/2024	NON-COMPETING CONTINUATION	-$5,074
														Subtotal = $332,561

Issue Date FY: 2023 ( Subtotal = $332,561 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	002	5	7/21/2023	COMPETING CONTINUATION	$332,561
2023	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	4	3/10/2023	NON-COMPETING CONTINUATION	$0
2023	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	001	4	7/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $332,561

Issue Date FY: 2021 ( Subtotal = $377,179 )
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	4	4/15/2021	NON-COMPETING CONTINUATION	$377,179
														Subtotal = $377,179

Issue Date FY: 2020 ( Subtotal = $371,706 )
2020	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	3	3/30/2020	NON-COMPETING CONTINUATION	$311,500
2020	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	001	3	6/11/2020	SUPPLEMENT FOR EXPANSION	$60,206
														Subtotal = $371,706

Issue Date FY: 2019 ( Subtotal = $311,500 )
2019	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	2	4/15/2019	NON-COMPETING CONTINUATION	$311,500
														Subtotal = $311,500

Issue Date FY: 2018 ( Subtotal = $311,500 )
2018	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	1	7/19/2018	NEW	$311,500
														Subtotal = $311,500

Grand Total All Awards = $2,369,568

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An analysis of the regulation and functions of a novel family of membraneless organelles in eukaryotic cells

Award Number: R01GM128440

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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