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Decoding and Reprogramming Redox Signal Transduction Pathways

Award Number: R35GM138277
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: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Decoding and Reprogramming Redox Signal Transduction Pathways - Project Summary Cells have evolved intricate enzymatic machineries that help them exist and survive redox stresses in their microenvironment. Enzymatic redox sensing, signaling, and response mechanisms are critical for a diverse set of physiological processes in all forms of life ranging from bacteria and plants to humans. Unlike other cellular signaling processes, redox signaling involves highly reactive reagents such as nitric oxide (NO), carbon monoxide (CO), and reactive oxygen species that raise concerns regarding the potential of these reagents for participation in other non-specific reactions. Yet, such side reactions are uncommon under physiological conditions suggesting high specificity and selectivity of enzymatic redox signal transduction pathways. In turn, we ask the following two pertinent questions: a) What makes redox signaling pathways so specific? and b) Can we rationally and systematically reprogram redox signal transduction pathways to re-instate/disrupt cellular redox balance? These questions have been largely overlooked from biological and inorganic chemistry perspective, even though redox imbalances are responsible for a variety of diseases ranging from neurological disorders to cancer. Our lab focuses on these paradigm shifting questions and the long-term goal of our research program is to develop molecular strategies that reprogram sensing/signaling mechanisms of biological redox reagents involved in human health and disease. In this grant period, we focus on heme iron-based DosS and DosT enzymes that sense low O2 or NO or CO in the bacterial microenvironment to signal dormancy as a response. Using our combined expertise in metalloprotein structure-function studies, protein engineering, enzymology and spectroscopy, we will develop structure-guided protein design approaches to reprogram the redox stimuli sensitivity and specificity of these enzymes as well as understand the implications of such modulations on redox signaling and cellular behavior. We will also use cutting-edge structural biology techniques to investigate the structural/molecular basis of signal transduction in these enzymes. Finally, we will develop redox-selective activity-based probes to quantify active/inactive sensor levels in the cell. Overall, our findings will not only provide a fundamental understanding of cellular redox sensing and signaling mechanisms, but also inform on mechanisms to modulate cellular physiology and phenotypic responses. Health Relevance: Maintenance of a normal intracellular redox status is crucial for regulating physiological responses. Any imbalance in this status results in a variety of diseases such as cancer, cardiovascular and neurological disorders. Our research program aims to design molecular approaches that reprogram the ability of cells to sense and signal redox changes in their environment. These approaches could be applied to re-instate cellular redox homeostasis in diseased states.


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 = $423,500 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Biomedical Research and Research Training	000	6	3/12/2026	COMPETING CONTINUATION	$423,500
														Subtotal = $423,500

Issue Date FY: 2024 ( Subtotal = $488,207 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	5	8/14/2024	SUPPLEMENT FOR EXPANSION	$106,248
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	5	7/10/2024	NON-COMPETING CONTINUATION	$381,959
														Subtotal = $488,207

Issue Date FY: 2023 ( Subtotal = $382,095 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	4	6/28/2023	NON-COMPETING CONTINUATION	$382,095
														Subtotal = $382,095

Issue Date FY: 2022 ( Subtotal = $383,106 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	3	6/14/2022	NON-COMPETING CONTINUATION	$383,106
														Subtotal = $383,106

Issue Date FY: 2021 ( Subtotal = $541,683 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	2	7/9/2021	SUPPLEMENT FOR EXPANSION	$181,226
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	2	5/20/2021	NON-COMPETING CONTINUATION	$360,457
														Subtotal = $541,683

Issue Date FY: 2020 ( Subtotal = $359,096 )
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	1	7/10/2020	NEW	$359,096
														Subtotal = $359,096

Grand Total All Awards = $2,577,687

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Decoding and Reprogramming Redox Signal Transduction Pathways

Award Number: R35GM138277

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: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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