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Fluorescence tools that illuminate biology and inspire translation

Award Number: R35GM134963
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: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Fluorescence tools that illuminate biology and inspire translation - Project Summary: Our lab works at the interface of chemistry, biology, and medicine. I am drawn to new or complex biological systems whose chemistry and/or mechanism is incompletely understood. New and complex biology is replete with opportunities for fundamental discovery, and history has taught that fundamental discoveries are often accompanied by unexpected therapeutic insights. Efforts on two complex systems comprise my NIGMS portfolio. The first is the organelle interactome, the system of inter-membrane contacts that directly or indirectly control virtually all cell function]. Despite its unquestioned importance, the organelle interactome–especially its dynamics–remains poorly characterized because there are so few useful tools. Visualizing organelle dynamics in live cells for biologically relevant times, especially at resolutions < 100 nm, was impossible, let alone in multiple colors. We developed HIDE probes to fill this void. We discovered that tethering a fluorophore to an organelle membrane via a lipid (rather than a membrane protein) improves imaging time by as much as 50-fold. Even better, as HIDE probes are composed of cell-permeant small molecules, they interrogate cells that are difficult or impossible to modify genetically. We made great progress in the last period developing and applying HIDE probes for imaging. Here we broaden their utility for multi-organelle (>2) HIDE fluorescence lifetime imaging microscopy; to deliver photocatalyst proximity labeling tools; and to sequester and inactivate difficult to target disease-causing proteins. The second portion of my NIGMS portfolio focuses on understanding and improving macromolecule delivery, the single most important bottleneck hindering the development of next-gen biologic therapies. The delivery problem can be summed up in one phrase: inefficient endosomal escape. In previous NIGMS-funded work, we identified a mini-protein (ZF5.3) that is actively endocytosed and escapes the endocytic pathway with unprecedented efficiency. We learned much about ZF5.3 during the last period. Using fluorescence correlation spectroscopy (FCS), a state-of-the-art single molecule method, we learned that ZF5.3 escapes from late endosomes through a previously unrecognized portal (HOPS), and is most efficient when conjugated to cargo that are small or unfold easily. We also discovered that ZF5.3 itself unfolds in late endosomes and unfolding is required for HOPS-mediated endosomal escape. Here we build on these discoveries to develop scaffolds for genuinely cell-permeant protein interaction inhibitors; others that escape earlier along the endocytic pathway and deliver compact gene-editing tools; and probe the mechanism of endosomal escape in vitro and in cellulo.


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 = $691,843 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	119 CALIFORNIA HALL	BERKELEY	CA	94720	ALAMEDA	USA	Biomedical Research and Research Training	001	7	5/6/2026	NON-COMPETING CONTINUATION	$691,843
2026	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	119 CALIFORNIA HALL	BERKELEY	CA	94720	ALAMEDA	USA	Biomedical Research and Research Training	000	5	4/8/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $691,843

Issue Date FY: 2025 ( Subtotal = $691,843 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	002	6	7/23/2025	COMPETING CONTINUATION	$691,843
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	5	7/15/2025	NON-COMPETING CONTINUATION	$0
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	5	11/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $691,843

Issue Date FY: 2024 ( Subtotal = $690,373 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	5	5/20/2024	NON-COMPETING CONTINUATION	$69,037
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	5	2/8/2024	NON-COMPETING CONTINUATION	$621,336
														Subtotal = $690,373

Issue Date FY: 2023 ( Subtotal = $706,184 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	4	2/9/2023	NON-COMPETING CONTINUATION	$690,373
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	4	5/5/2023	SUPPLEMENT FOR EXPANSION	$15,811
														Subtotal = $706,184

Issue Date FY: 2022 ( Subtotal = $690,373 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	3	2/23/2022	NON-COMPETING CONTINUATION	$621,336
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	3	6/24/2022	NON-COMPETING CONTINUATION	$69,037
														Subtotal = $690,373

Issue Date FY: 2021 ( Subtotal = $815,101 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	2	7/27/2021	SUPPLEMENT FOR EXPANSION	$127,262
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	2	3/5/2021	NON-COMPETING CONTINUATION	$687,839
														Subtotal = $815,101

Issue Date FY: 2020 ( Subtotal = $453,649 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	1	1/29/2020	NEW	$453,649
														Subtotal = $453,649

Grand Total All Awards = $4,739,366

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Fluorescence tools that illuminate biology and inspire translation

Award Number: R35GM134963

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: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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