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The Genetic Basis of Variation in Post-Transcriptional Regulation of Stress Defense

Award Number: R35GM161393
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: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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The Genetic Basis of Variation in Post-Transcriptional Regulation of Stress Defense - PROJECT SUMMARY Cellular stress responses are critical for maintaining internal homeostasis in the face of environmental assaults. Regulation of stress responses is remarkably complex, and post-transcriptional and post-translational processes that govern stress defense are especially poorly understood. An integrated and mechanistic understanding of the full suite of regulatory strategies that govern stress defenses is critical, as defects in stress defense have been linked to many human disorders ranging from cancer to neurodegenerative disease. Likewise, we know that regulatory variation has been linked to a large number of human disorders, but the vast majority of studies on regulatory variation have focused on mRNA levels. This R35 application represents the intersection of these two themes: how do cells sense and respond at the post-transcriptional level to stressful environments, and how does post-transcriptional regulatory variation contribute to individual stress susceptibility or resilience? We will answer these questions using the powerful tools of the budding yeast Saccharomyces cerevisiae. Our strategy over the next five years is to apply quantitative and high-throughput genetic approaches to understand the genetic basis and functional consequences of post-transcriptional regulatory variation. This will include different linkage mapping approaches to explore the genetic basis of natural variation in the post-transcriptional response to stress. At the post-translational level, we will explore the genetic architecture of natural variation in global lysine acetylation patterns, a key post-translational modification implicated in stress defense, during the yeast heat shock response. Causal effects of identified variants will be tested by allele swap experiments, and we will characterize allelic effects on different aspects of fitness during stress. Finally, we will use high-throughput CRISPR screening to interrogate the effects of acetyl-mimetic mutations for all known acetyl-lysine sites across diverse strain backgrounds. Ultimately, this work will help generate a better understanding of post-transcriptional and post-translational stress responses, while informing on mechanisms for why individuals with certain genetic backgrounds are more resilient or more sensitive to stress.


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 = $401,254 )
2026	2026	UNIVERSITY OF ARKANSAS	1125 W MAPLE ST STE 316	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Biomedical Research and Research Training	000	1	7/30/2026	NEW	$401,254
														Subtotal = $401,254

Grand Total All Awards = $401,254

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The Genetic Basis of Variation in Post-Transcriptional Regulation of Stress Defense

Award Number: R35GM161393

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: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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