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Designer Molecular Probes for Biomedical Applications

Award Number: R35GM131907
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: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Designer Molecular Probes for Biomedical Applications - PROJECT SUMMARY For two decades the PI has led a research program developing molecular probes that have yielded breakthroughs in Chemical Biology, Radiology, Cellular Genomics/Transcriptomics, Anesthesiology, and Photochemistry. Since 2019, the PI has published 20 peer-reviewed research manuscripts and 2 review articles with NIH-MIRA support, and several related papers. The PI has mentored 2 postdoctoral fellows to successful job placement, 4 graduate students to Ph.D. completion and chemistry careers, and 6 undergraduates to STEM Ph.D. programs. The MIRA grant continues to provide primary support to 8 graduate students and 2 undergraduates who are carrying out the studies that underpin this renewal application. The PI’s service confirms a strong commitment to scientific review, undergraduate and graduate education, outreach, community building, and junior faculty mentoring. This MIRA grant renewal will build on several exciting advances made in the current funding cycle. In the first project, several new small-molecule capsules and proteins have been developed for xenon binding. Key principles have been elucidated for controlling the xenon exchange rate in these systems, and a suite of new tools will drive the development of sensitive xenon contrast agents (Xe CAs) for molecular imaging and also lead to improved understanding of xenon anesthesia and analgesia. Critically, the FDA approved hyperpolarized Xe-129 for human lung magnetic resonance imaging (MRI) in Dec, 2022. Imaging equipment has been assembled at UPenn with collaborators (Kadlecek and Gade), and we propose to perform cutting-edge Xe-129 MRI studies and investigate Xe CAs developed in the PI’s laboratory for lung cancer detection in mice. Notably, a Xe CA employing ribose-binding protein (RBP) led to the discovery of 5 mM ribose in HeLa cells, 1000x more than previously estimated. This has spawned a second project, which is the development of the first useful fluorescence resonance energy transfer (FRET)-based sensor for real-time quantitation of ribose levels in mammalian cells. This offers the opportunity to study natural fluctuations in ribose (likely as a function of cell cycle), and also explore enzymatic pathways that we hypothesize convert ribose-5-phosphate (originating from the pentose phosphate pathway) to ribose. Finally, a third project stems from the development of fluorescein- and Cy5-labeled siRNA molecules as first-in-class ratiometric pH probes for elucidating details of endosomal entrapment and release and improving delivery of therapeutic oligonucleotides to skeletal muscle. Novel bicyclic oligonucleotides are proposed for achieving potent enzyme inhibition.


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 = $741,257 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	6	4/30/2025	COMPETING CONTINUATION	$741,257
2025	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	4/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $741,257

Issue Date FY: 2023 ( Subtotal = $598,996 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	8/4/2023	NON-COMPETING CONTINUATION	$598,996
														Subtotal = $598,996

Issue Date FY: 2022 ( Subtotal = $848,996 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	5/26/2022	SUPPLEMENT FOR EXPANSION	$250,000
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	4	8/24/2022	NON-COMPETING CONTINUATION	$598,996
														Subtotal = $848,996

Issue Date FY: 2021 ( Subtotal = $598,996 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	8/9/2021	NON-COMPETING CONTINUATION	$598,996
														Subtotal = $598,996

Issue Date FY: 2020 ( Subtotal = $597,703 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	2	8/19/2020	NON-COMPETING CONTINUATION	$597,703
														Subtotal = $597,703

Issue Date FY: 2019 ( Subtotal = $727,444 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	8/22/2019	NEW	$727,444
														Subtotal = $727,444

Grand Total All Awards = $4,113,392

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Designer Molecular Probes for Biomedical Applications

Award Number: R35GM131907

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: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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