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Identification of Genetic Suppressors of RNA Granules

Award Number: R03AG077140
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Identification of Genetic Suppressors of RNA Granules - SUMMARY/ABSTRACT Polyadenylated (Poly(A)+) RNA containing cytoplasmic granules affect numerous biological functions and disease states. In normal cells, poly(A)+ granules take many forms, such as stress granules (SGs), processing bodies (PBs), neuronal granules, and germ cell granules. These granules affect mRNA localization, stability, and/or translational control under various physiological contexts. Pathogenic protein aggregates are a unifying feature of many neurodegenerative diseases (ND), including amyotrophic lateral sclerosis (ALS). The relationships between normal and pathogenic aggregates is still being deciphered, however clear links between the two are known. Thus, the co-aggregation of poly(A)+ RNA and protein in cytoplasmic granules under both normal and disease conditions is of broad biological importance. Yet, the genetic suppressors of poly(A)+ RNA granule formation have not been identified on a genome-wide scale. The long-term goal of this research program is to understand both the genetic and the environmental factors that regulate SG formation, and to understand how SGs relate to other types of aggregates and disease states. The overarching hypothesis is that genetic regulators of poly(A)+ RNA granule formation can be used to modulate RNA granule formation in specific biological and disease-related contexts. As a first step to testing this hypothesis, the primary objective of this proposal is to perform whole-genome screening to identify genes that suppress poly(A)+ RNA granule formation in both Drosophila and human cells. RNA granule suppressing genes, when depleted by RNAi, will cause the spontaneous formation of poly(A)+ RNA granules. To obtain the primary objective, the following two specific aims will be pursued. Aim 1: To identify genes that suppress poly(A)+ RNA granules in Drosophila S2R+ cells. An image analysis pipeline will be adapted to re-analyze images from a previously published whole-genome RNAi screen in Drosophila S2R+ cells (Farny et al., 2008). Aim 2: To examine the evolutionary conservation of poly(A)+ RNA granule suppressors in human cells. Using the primary screen hits from Aim 1 as a guide, a targeted CRISPR knockout library will be screened to identify human genes that suppress poly(A)+ RNA granules U2OS cells. This aim will also address the working hypothesis that genetic silencing of poly(A)+ RNA granule suppressors will result in an increase in endogenous TDP-43 aggregation in U2OS cells. The rationale for this approach is that, given the known links between poly(A)+ RNA granules and disease-causing aggregates, suppressors of poly(A)+ aggregation could be harnessed in future studies to suppress pathogenic aggregates. Given the known links between normal and pathogenic aggregate formation, understanding the genetic determinants of poly(A)+ RNA granule formation will provide new avenues of investigation for the genetic control of pathogenic aggregate formation. Thus the knowledge gained here will be of broad interest and importance.


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 = $0 )
2025	2023	WORCESTER POLYTECHNIC INSTITUTE	100 INSTITUTE RD	WORCESTER	MA	01609	WORCESTER	USA	Aging Research	000	2	6/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $73,580 )
2023	2023	WORCESTER POLYTECHNIC INSTITUTE	100 INSTITUTE RD	WORCESTER	MA	01609	WORCESTER	USA	Aging Research	000	2	3/6/2023	NON-COMPETING CONTINUATION	$73,580
														Subtotal = $73,580

Issue Date FY: 2022 ( Subtotal = $73,677 )
2022	2022	WORCESTER POLYTECHNIC INSTITUTE	100 INSTITUTE RD	WORCESTER	MA	01609	WORCESTER	USA	Aging Research	000	1	5/19/2022	NEW	$73,677
														Subtotal = $73,677

Grand Total All Awards = $147,257

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Identification of Genetic Suppressors of RNA Granules

Award Number: R03AG077140

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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