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Dissecting the Mechanisms of Regulation and Quality Control in Ribosome Assembly and the Consequences of their Failure

Award Number: R35GM136323
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Ribosomes carry out protein synthesis in all cells, interpreting the information contained in the mRNA to produce the proper amount of the correct protein. In addition, ribosomes also mediate mRNA quality control. Thus, misassembled ribosomes can affect the sequence and abundance of proteins and mRNAs, thereby disrupting protein homeostasis. This can lead to a number of diseases, demonstrating the importance of ensuring ribosomes are accurately assembled, and produced in the correct numbers. Using a combination of biochemical, genetic, genomic and structural tools, we will (i) investigate mechanisms that promote proper incorporation of ribosomal proteins and folding of the RNA, (ii) dissect quality control pathways to identify and ultimately degrade misassembled intermediates and (iii) study how misassembled ribosomes promote disease. In the first part, we will build on our existing work and study the late assembly of the ribosomal head, as well as combine insights from recent structures and our biochemical work to understand how DEAD-box proteins are used to construct ATP-dependent regulatory switches to control major conformational transitions in early 40S biogenesis. In the second part, we will extend our work on quality control to investigate a possible proofreading mechanism and identify degradation pathways for misassembled intermediates, a novel frontier for the field. In the last part, we will investigate how ribosomes containing substoichiometric levels of two ribosomal proteins, Asc1 and Rps10, which are produced in cancer cells that lack sufficient amounts of the assembly factor Ltv1, promote disease. This work builds on a genetic system we have developed to separate ribosomes of distinct composition, and also takes into consideration the known roles of these proteins in mRNA quality control. In addition, we will also investigate the effects from dysregulation of ribosome numbers in disease. Together, the proposed work will link mechanistic insights into a fundamental problem of cell and molecular biology – how ribosomes are assembled, to human disease.


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: 2023 ( Subtotal = $952,090 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	002	5	5/19/2023	NON-COMPETING CONTINUATION	$952,090
2023	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	3	11/18/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$57,399
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	2	11/18/2022	NON-COMPETING CONTINUATION	-$57,399
														Subtotal = $952,090

Issue Date FY: 2022 ( Subtotal = $977,642 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	002	4	6/7/2022	NON-COMPETING CONTINUATION	$952,090
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	2	4/28/2022	NON-COMPETING CONTINUATION	-$576,475
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	3	5/2/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$602,027
														Subtotal = $977,642

Issue Date FY: 2021 ( Subtotal = $911,680 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	2	5/17/2021	NON-COMPETING CONTINUATION	$911,680
														Subtotal = $911,680

Issue Date FY: 2020 ( Subtotal = $868,507 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	1	5/11/2020	NEW	$868,507
														Subtotal = $868,507

Grand Total All Awards = $3,709,919

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Dissecting the Mechanisms of Regulation and Quality Control in Ribosome Assembly and the Consequences of their Failure

Award Number: R35GM136323

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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