Thursday, November 21, 2024 11/21/2024

Six-Dimensional Single-Molecule Nanoscopy for Elucidating the Dynamic Organization of Biomolecules

Award Number: R35GM124858
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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7. PROJECT SUMMARY The goal of the proposed MIRA-funded research portfolio is to discover how dynamic interactions between individual biomolecules at the nanoscale influence their collective function and organization in complex biophysical processes. The proposed research program integrates continued development of 6D single- molecule (SM) imaging (3D positions and 3D orientations) with mechanistic studies of the organization of biomolecular interactions at the nanoscale. Importantly, the proposed scientific goals synergistically spur the development of impactful imaging capabilities, and these new capabilities will in-turn overcome barriers to enable novel significant scientific trajectories to be pursued. Four broad research thrusts will be pursued. Thrust 1 will develop smart adaptive 6D nanoscopy. Previous studies have shown that fixed imaging systems cannot measure all possible molecular rotational motions with the best-possible quantum-limited precision. Thus, dynamic illumination and fluorescence modulation hardware will be integrated to enable the imaging system to adapt as data is collected. Fusing model-driven design algorithms with data-driven deep learning methods will yield smart microscopes that enable measurements that are not possible even with current state-of-the-art nanoscopes. Thrust 2 will develop high-speed 6D SM tracking to map spatial heterogeneities in molecular interactions between biomolecules. These heterogeneities govern important processes like phase separation, but current techniques have sufficient spatiotemporal resolution to resolve mechanistic details. Time-varying illumination, single-photon counting, and direct pupil imaging will be integrated to visualize these dynamics using 10x fewer emission photons and thus 10x faster speed than state-of-the art methods. Thrust 3 will leverage developments in 6D nanoscopy to elucidate dynamic molecular architectures of self- assembling peptides and natural amyloidogenic proteins. Critically, scientists must disentangle the effects of peptide sequence, secondary structure, assembly architecture, and aggregation conditions to create new biomaterials for diagnostics and therapeutics, as well as to elucidate the mechanisms of cytotoxicity in amyloid diseases. The 6D positions and orientations of transiently binding fluorophores will visualize the dynamic organization of individual peptide assemblies both in vitro and as they interact with living cells with nanoscale resolution. Thrust 4 will leverage developments in 6D SM tracking to visualize heterogeneous network architectures within biomolecular condensates that ensemble measurements fail to detect. The 6D positions and orientations of fluorogenic probes will be used to characterize the network architecture of stickers and spacers within the condensate, thereby visualizing the driving forces of phase separation. Six-dimensional SM nanoscopy will also directly observe how proteins are recruited and reorganized throughout the phase separation process, leading to mechanistic insights into the formation and spatiotemporal evolution of biomolecular condensates.


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	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	7	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $388,750 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Biomedical Research and Research Training	002	7	6/19/2024	NON-COMPETING CONTINUATION	$38,875
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Biomedical Research and Research Training	001	7	4/8/2024	NON-COMPETING CONTINUATION	$349,875
2024	2021	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	5	4/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $388,750

Issue Date FY: 2023 ( Subtotal = $466,222 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	001	6	4/27/2023	COMPETING CONTINUATION	$466,222
2023	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	5	4/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $466,222

Issue Date FY: 2021 ( Subtotal = $321,862 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	5	7/27/2021	NON-COMPETING CONTINUATION	$321,862
														Subtotal = $321,862

Issue Date FY: 2020 ( Subtotal = $321,862 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	4	7/24/2020	NON-COMPETING CONTINUATION	$321,862
														Subtotal = $321,862

Issue Date FY: 2019 ( Subtotal = $322,969 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	3	8/1/2019	NON-COMPETING CONTINUATION	$322,969
														Subtotal = $322,969

Issue Date FY: 2018 ( Subtotal = $322,969 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	2	7/31/2018	NON-COMPETING CONTINUATION	$322,969
														Subtotal = $322,969

Issue Date FY: 2017 ( Subtotal = $350,620 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	1	8/11/2017	NEW	$350,620
														Subtotal = $350,620

Grand Total All Awards = $2,495,254

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Six-Dimensional Single-Molecule Nanoscopy for Elucidating the Dynamic Organization of Biomolecules

Award Number: R35GM124858

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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