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Mechanisms of translation response to stress

Award Number: R35GM162154
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: 02/13/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Mechanisms of translation response to stress - ABSTRACT Regulation of mRNA translation is vital for cells to acclimate and respond to changing environments and stress. A paradoxical mechanism of protein synthesis regulation is the modulation of translational fidelity. Mounting evidence shows that organisms, from bacteria to humans, regulate errors during translation to resist and acclimate to cellular stresses. Despite recent progress and exciting discoveries, our understanding of how trans- lational fidelity is regulated remains incomplete. The long-term objective of my research program is to determine how and why changes in translational fidelity occur and the molecular mechanisms underlying its regulation. In this MIRA proposal, we focus on the function of two families of translation factors: a rare tryptophanyl-tRNA synthetase (TrpRS) and an aminoacyl-tRNA deacylase (CtdA). Our preliminary and published results indicate that these protein factors coordinate translational fidelity in response to environmental and physiological changes. TrpRS is a universal and essential enzyme that ligates tryptophan to tRNAs during protein synthesis. TrpRS’s substrate specificity is critical in translational fidelity as ligation of non-cognate amino acids causes translation errors. Our preliminary data show that some organisms, including pathogens of public health interest, such as Salmonella enterica and Klebsiella pneumoniae, encode an unconventional TrpRS (named TrpRS-B2) with relaxed specificity that confers resistance against oxidative stress. TrpRS-B2 is predominantly found in organisms encoding an additional TrpRS (TrpRS-B1) that lacks the characteristics of TrpRS-B2. CtdA is a newly discovered family of aminoacyl-tRNA deacylases that maintain translational fidelity of Arg codons. CtdA hydrolyzes canavanyl-tRNAArg resulting from the ligation of canavanine, a toxic non-standard amino acid, to tRNAArg by arginyl-tRNA synthetase, which confuses canavanine with Arg. However, little else is known about the potential involvement of CtdA in other cellular functions and its diversification during evolution. The emphasis of our proposed research is to establish how TrpRS-B2 and CtdA contribute to the biology of several human-associated bacteria by regulating translation. In the next five years, we will address several fundamental questions using Salmonella enterica as a model organism because it offers a facile and established system to interrogate diverse environmental, physiological, and host-interaction conditions. We will investigate the molecular and biochemical differences between TrpRS-B2 and TrpRS-B1 and how TrpRS-B2 confers toler- ance to oxidative stress and promotes virulence. Moreover, we will examine the role(s) of CtdA beyond canavanine detoxification and the function of newly identified CtdA paralogs. These studies will shed light on the diverse regulatory mechanisms of translational fidelity and expand our understanding of the survival strategies of bacteria. Ultimately, this knowledge can help develop new approaches to treating human bacterial diseases.


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: 2026 ( Subtotal = $457,875 )
2026	2026	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Biomedical Research and Research Training	000	1	2/13/2026	NEW	$457,875
														Subtotal = $457,875

Grand Total All Awards = $457,875

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Mechanisms of translation response to stress

Award Number: R35GM162154

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: 02/13/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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