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Design of Fe2+ and H2O2 Induced Proximity Functionalized Imaging Probes for the Control of Cellular Functions

Award Number: R01GM130772
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: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Design of Fe2+ and H2O2 Induced Proximity Functionalized Imaging Probes for the Control of Cellular Functions - Project Summary Gene/cell therapies finally come of age thanks to the fundamental advances made by innovative and improved biotechnologies. Nonetheless, many challenges particularly toxicity and undesired/uncontrolled immune response remain. This research proposal addresses these concerns and represents a critical first step toward developing novel, more effective cell/gene therapy. Toward this end, we propose a novel synthetic biology technology termed “Environment Stimuli-Induced Proximity (ESIP)” to spatiotemporally manipulate cellular functions. The new strategy can overcome the difficulty of the established chemically induced proximity (CIP) method to mediate the translation of endogenous cellular signals into tailored cellular functions with spatiotemporal precision. To demonstrate the feasibility, we propose to develop fluorescent and chemiluminescent Fe(II) and H2O2 responsive ESIP chemical inducers because Fe(II) and H2O2 are important signal molecules, which are associated with numerous biological functions and diseases, and gibberellin (GA) and abscisic acid (ABA) are established chemical inducers with low toxicity. Specifically, we will design, synthesize, test and optimize Fe2+ and H2O2-responsive fluorescent and chemiluminescent ESIP inducers (Specific Aims 1-2) and test them in cells and construct ESIP-mediated “AND” Boolean logic gates to control the conditional production of AD therapeutic proteins (Specific Aim 3). These studies will prove that these `smart' theranostic probes possess the ability to sense endogenous Fe(II) and H2O2 specifically, and the ability to trigger the release of original bioactive chemical inducers GA and ABA, which then induce downstream biological functions such as luciferase expression and the production of neuron protective BDNF proteins. The technology will ultimately be transformed into entirely new cell/gene therapies for disease treatment with significantly reduced side effects. It is expected that this powerful and general strategy can be integrated with a variety of existing synthetic biology molecular parts and tools to build new cellular genetic and signaling circuitries to generate new functions as toolbox for biomedical research and as therapeutics for various disease treatment.


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 = $0 )
2025	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Biomedical Research and Research Training	000	4	11/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Biomedical Research and Research Training	000	4	8/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $287,164 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Biomedical Research and Research Training	000	4	3/31/2022	NON-COMPETING CONTINUATION	$258,448
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Biomedical Research and Research Training	001	4	7/21/2022	NON-COMPETING CONTINUATION	$28,716
														Subtotal = $287,164

Issue Date FY: 2021 ( Subtotal = $287,504 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Biomedical Research and Research Training	000	3	4/8/2021	NON-COMPETING CONTINUATION	$287,504
														Subtotal = $287,504

Issue Date FY: 2020 ( Subtotal = $404,333 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Biomedical Research and Research Training	001	2	9/18/2020	SUPPLEMENT FOR EXPANSION	$116,500
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Biomedical Research and Research Training	000	2	4/7/2020	NON-COMPETING CONTINUATION	$287,833
														Subtotal = $404,333

Issue Date FY: 2019 ( Subtotal = $300,749 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Biomedical Research and Research Training	000	1	4/18/2019	NEW	$300,749
														Subtotal = $300,749

Grand Total All Awards = $1,279,750

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Design of Fe2+ and H2O2 Induced Proximity Functionalized Imaging Probes for the Control of Cellular Functions

Award Number: R01GM130772

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: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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