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Engineering fluorescence and magnetic resonance reporter genes for imaging biological function in hypoxic cells and in vivo

Award Number: R35GM133530
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary One of the most powerful approaches for studying biological function relies on the use of genetically encoded light-emitting proteins to visualize cell physiology. However, existing reporter genes - the prototypical green fluorescent protein (GFP) and luciferase - have two major limitations. First, oxidation by molecular oxygen is central to the mechanism by which GFP, luciferase, and derivative reporters emit light. Second, optical photons are scattered and absorbed by opaque tissue, which effectively blocks light penetration in intact animals. As a result, GFP and luciferase based reporters fail to produce light in complex settings such as hypoxia (oxygen < 1%) or deep inside intact animals. An immediate impact of these shortcomings is on medical research. Hypoxia plays a central role in the pathophysiology of tumors and polymicrobial infections with consequences ranging from drug resistance to inflammation. To understand how hypoxia reprograms cell function in these contexts, there is a need for reporter gene technologies that allow biological activity to be dynamically studied in hypoxic cell cultures. Likewise, to understand processes such as tumor biology in their important in vivo context, there is a need for reporter genes that are compatible with optically opaque animals. The goal of our research program is to address these long-standing challenges in biological imaging. To do so, our research will pursue the development of new classes of reporter genes for noninvasive imaging of biological function in hypoxic cell cultures (in vitro) and in live animals (in vivo). Our proposed approach builds on proteins with special properties – photoreceptors, paramagnetic enzymes, and water channels – and applies molecular engineering to develop new reporters for fluorescence and magnetic resonance imaging (MRI). Our research program proposes five core objectives: 1) engineering bright, multi-colored, oxygen-independent fluorescent proteins for hypoxia, 2) developing sensitive and multiplexable MRI reporters for in vivo imaging, 3) designing bioresponsive sensors based on these proteins to detect cell metabolites and gene expression, 4) applying these sensors to study antibiotic tolerance in hypoxic bacteria, and 5) induction of specialized treatment resistant cancer cells in glioblastoma tumors. Success in these goals will provide a breakthrough technique for studying a broad spectrum of biological processes where hypoxia and in vivo milieu provide important pathophysiological contexts.


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: 2023 ( Subtotal = $330,014 )
2023	2023	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	5	9/14/2023	NON-COMPETING CONTINUATION	$330,014
														Subtotal = $330,014

Issue Date FY: 2022 ( Subtotal = $326,461 )
2022	2022	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	4	8/19/2022	NON-COMPETING CONTINUATION	$326,461
														Subtotal = $326,461

Issue Date FY: 2021 ( Subtotal = $312,398 )
2021	2021	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	3	9/8/2021	NON-COMPETING CONTINUATION	$312,398
														Subtotal = $312,398

Issue Date FY: 2020 ( Subtotal = $330,014 )
2020	2020	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	2	9/18/2020	NON-COMPETING CONTINUATION	$330,014
														Subtotal = $330,014

Issue Date FY: 2019 ( Subtotal = $348,667 )
2019	2019	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	1	8/21/2019	NEW	$348,667
														Subtotal = $348,667

Grand Total All Awards = $1,647,554

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Engineering fluorescence and magnetic resonance reporter genes for imaging biological function in hypoxic cells and in vivo

Award Number: R35GM133530

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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