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An Activity-Based Biomolecule Labeling Platform for the Imaging of Cells and Tissues Under Oxidative Stress

Award Number: R00GM143573
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: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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An Activity-Based Biomolecule Labeling Platform for the Imaging of Cells and Tissues Under Oxidative Stress - Project Summary Reactive oxygen species (ROS) are a family of small-molecules in living systems that serve vital roles in both signaling and stress. Hydrogen peroxide (H2O2), superoxide (O2•-), and hypochlorous acid (HOCl), among others, are all examples of ROS that have been traditionally viewed as sources of oxidative stress and damage. Aberrant ROS production contributes to a multitude of pathologies such as neurodegeneration, cancer, and cardiovascular disorders. However, ROS are also critical for maintaining metabolic homeostasis through activation of multiple classes of proteins. This signal-stress dichotomy, coupled with the small and transient nature of ROS, presents a challenge when attempting to decode the complex landscape of cellular redox homeostasis. Fluorescent probes are frequently employed to visualize ROS in living systems through fluorescence microscopy, however these probes are prone to diffusion after ROS detection. This leads to inaccurate determination of ROS localization and poor signal-to-noise responses. As such, there is a need to create probes amenable to the permanent recording of ROS via fluorescence imaging. We hypothesize that activity-based cell-trappable fluorescent probes can be used as a platform to gain further understanding of ROS-mediated inter- and intra- cellular signaling. We propose three specific aims to test this hypothesis. First, we will synthesize fluorophores caged with activity-based triggers and proximal fluoromethyl groups to serve as latent equivalents of quinone methide upon ROS sensing. ROS responsive uncaging will allow for the fluorescent labeling of adjacent biomolecules. Second, we will apply our probes across multiple model live cell lines to monitor ROS fluxes. We will also map cell-to-cell communication mediated by ROS using microglia-neuron co-culture as a biological model. This system will allow us to probe transcellular redox signaling as microglia can be selectively activated in the presence of neurons thereby dispatching H2O2 to nearby neurons. The third aim involves developing a fluorescent polymer amplification strategy to increase signal-to-noise responses of tandem activity-based sensing/labeling probes and will primarily be carried out in the R00 phase. Small- molecule polymer initiators will be caged in a similar manner to the previously described fluorescent probes. After ROS sensing and biomolecule labeling, polymerization will be performed to generate fluorescent polymers from biomolecule surfaces thus enabling signal amplification and visualization. This strategy will be carried over into live cell lines described above. This research fits into the applicant’s goal of establishing a program which uses polymer chemistry to probe fundamental questions in biological systems.


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 = $237,110 )
2025	2025	UNIVERSITY OF DELAWARE	550 S COLLEGE AVE	NEWARK	DE	19713	NEW CASTLE	USA	Biomedical Research and Research Training	000	5	7/10/2025	NON-COMPETING CONTINUATION	$237,110
														Subtotal = $237,110

Issue Date FY: 2024 ( Subtotal = $243,261 )
2024	2024	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Biomedical Research and Research Training	001	4	7/31/2024	NON-COMPETING CONTINUATION	$243,126
2024	2023	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Biomedical Research and Research Training	000	3	2/21/2024	EXTENSION WITH OR WITHOUT FUNDS	$135
														Subtotal = $243,261

Issue Date FY: 2023 ( Subtotal = $248,955 )
2023	2023	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Biomedical Research and Research Training	000	3	8/30/2023	EXTENSION WITH OR WITHOUT FUNDS	$248,955
														Subtotal = $248,955

Grand Total All Awards = $729,326

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An Activity-Based Biomolecule Labeling Platform for the Imaging of Cells and Tissues Under Oxidative Stress

Award Number: R00GM143573

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: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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