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Cellular stress sensing via biomolecular condensation

Award Number: F31ES032337
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Cellular stress sensing via biomolecular condensation - Project Summary Background: Cells experience a wide array of environmental stresses, and must be able to sense and respond to changes in order to survive. The sensing process which occurs depends on the stress itself, and we have identified over 150 heat-sensitive proteins in S. cerevisiae which exhibit biomolecular condensation after temperature increase. Within this group, a conserved set of GTPases displays significant aggregation without the requirement of any other cellular components, opening up the possibility that these proteins have the ability to sense heat shock. Further, this set of proteins is connected to two fundamental functional responses which occur under heat stress -- transcriptional upregulation of heat shock genes and shutoff of ribosome biogenesis. Proteins that are highly sensitive to heat may act as long-unidentified sensors upstream of massive functional changes within the cell, and serve as heat sensing candidates for this proposal. Long viewed as a toxic consequence of harsh environmental conditions, recent work has shown that biomolecular condensate formation is non-random, adaptive, and reversible. With this emerging view, diseases like dementia and ALS which are associated with the accumulation of non-membrane bound protein aggregates might be the result of an aberrant activation of stress sensing pathways, indicating that our understanding of the disease pathology may need to be reevaluated. Specific Aims: 1: Are candidates sufficient to induce the transcriptional response in vivo? 2: What is the mechanism for heat sensing? 3: What is the functional relevance of candidate condensation on ribosome production? Study Design: I will take advantage of a cryophilic yeast which execute their heat-induced cellular responses at lower temperatures than S. cerevisiae. The cryophilic yeast likely contain homologous sensor proteins with increased sensitivity at lower temperatures. I will replace the endogenous sensor candidate genes with their cryophilic homologs and assay the ability of the recombinant S. cerevisiae to upregulate the production of heat- specific transcripts and attenuate ribosome biogenesis. I will reconstitute the components of these functional responses in vitro and test whether the condensation of candidate sensors can affect either response. Condensation of candidate sensors will also be studied in vitro using biochemical and biophysical assays to investigate their intrinsic ability to sense heat to describe the mechanistic underpinnings of sensing. Training: This research will be performed with Dr. D. Allan Drummond at the University of Chicago and will build upon my experimental skills by first characterizing the functional relevance of biomolecular condensation in environmental stress sensing and further expanding into understanding the biophysical mechanism. This training will prepare me for a future career studying how environmental stresses shape cellular behavior.


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 = -$9,951 )
2025	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Environmental Health	000	3	11/27/2024	NON-COMPETING CONTINUATION	-$9,951
														Subtotal = -$9,951

Issue Date FY: 2023 ( Subtotal = $31,847 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Environmental Health	000	3	12/23/2022	NON-COMPETING CONTINUATION	$31,376
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Environmental Health	001	3	2/27/2023	NON-COMPETING CONTINUATION	$471
														Subtotal = $31,847

Issue Date FY: 2022 ( Subtotal = $46,752 )
2022	2022	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Environmental Health	001	2	8/12/2022	NON-COMPETING CONTINUATION	$1,232
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Environmental Health	000	2	12/20/2021	NON-COMPETING CONTINUATION	$45,520
														Subtotal = $46,752

Issue Date FY: 2020 ( Subtotal = $45,520 )
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Environmental Health	001	1	8/17/2020	NEW	$0
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Environmental Health	000	1	8/13/2020	NEW	$45,520
														Subtotal = $45,520

Grand Total All Awards = $114,168

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Cellular stress sensing via biomolecular condensation

Award Number: F31ES032337

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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