Thursday, October 30, 2025 10/30/2025

Translational control of gene expression in fungi

Award Number: R01GM148702
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: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Translational control of gene expression in fungi - Summary Translation of mRNA is a central cellular process, but the mechanisms that control it are not fully understood. Up to 50% of eukaryotic mRNAs contain predicted upstream open reading frames (uORFs), but the roles of the vast majority of these uORFs remain undetermined. In some cases, we know that this additional translational capacity is evolutionarily conserved and serves critical functions in controlling gene expression. A special class of these conserved uORFs encodes peptides that stall protein synthesis in response to the presence of small metabolites. These nascent regulatory peptides act within the ribosome tunnel to arrest translation; by doing so, they control the production of enzymes important in metabolism. However, there remain important gaps in knowledge of the functions of uORFs. First, the mechanisms by which uORF-encoded peptides recognize small molecules and stall eukaryotic ribosomes to control gene expression remain unclear. Second, the extent to which uORFs are translated in cells under different conditions, the extent to which uORFs are evolutionarily conserved, and how and why the translation of particular uORFs controls gene expression, or if their translation serves other functions, is not known. To help bridge these gaps, we will determine the functions of a newly discovered conserved fungal uORF peptide named the inositol regulatory peptide (IRP). Our data indicate that the IRP regulates the expression of the first enzyme necessary for the synthesis of the important molecule inositol. We know that the IRP, while fungal in origin, can regulate reporter genes in mammalian cells as well as the fungus Neurospora crassa, in which we first discovered it. Using fungal and mammalian cell-free translation systems, we obtained direct evidence for translational control by the IRP. We will use both in vivo and in vitro approaches to determine the mechanism of action and physiological consequences of IRP function. In Aim 1, we will perform functional analyses to determine the mechanism of action of the IRP. In Aim 2, we will perform structural analyses to determine the mechanism of action of the IRP. Successful completion of the proposed work will provide mechanistic information that should significantly increase our understanding of translational control mechanisms that are generally important. It will provide new insights into regulatory and metabolic pathways that could be important for developing strategies to manipulate metabolism to improve human health and welfare.


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 = $303,751 )
2025	2025	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	3	7/15/2025	NON-COMPETING CONTINUATION	$303,751
														Subtotal = $303,751

Issue Date FY: 2024 ( Subtotal = $301,037 )
2024	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	2	7/10/2024	NON-COMPETING CONTINUATION	$301,037
														Subtotal = $301,037

Issue Date FY: 2023 ( Subtotal = $343,121 )
2023	2023	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	1	7/20/2023	NEW	$343,121
														Subtotal = $343,121

Grand Total All Awards = $947,909

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Translational control of gene expression in fungi

Award Number: R01GM148702

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: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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