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Mapping Transport Pathways through Nuclear Pores using 3D Super-Resolution Microscopy

Award Number: R01GM126190
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: 01/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Mapping Transport Pathways through Nuclear Pores using 3D Super-Resolution Microscopy - PROJECT SUMMARY Nuclear pore complexes (NPCs) mediate the bi-directional transport of proteins, RNAs and ribonucleoprotein complexes across the double-membrane nuclear envelope of eukaryotic cells. Consequently, NPCs are essential for the ability of many biosynthetic, signaling and gene regulatory processes to maintain cellular health and viability. Protein mis-localization due to recognition defects or altered NPC structure and function is linked to diseases as diverse as primary biliary cirrhosis, amyotrophic lateral sclerosis (ALS), leukemias and cancers, and Alzheimer's and Huntington's diseases. While the protein components of the NPC and many soluble nuclear transport factors have been identified and extensively studied, the mechanism(s) by which bi-directional transport occurs without clogging the pore remains unknown. The NPC has an octagonally symmetric approximately cylindrical structure with an hourglass-shaped central pore that has an internal minimal diameter of ~50-60 nm in humans. Occluding this pore and decorating its exits is a network of > 200 mobile intrinsically disordered polypeptides with thousands of phenylalanine-glycine (FG) repeat motifs that provide binding sites for the nuclear transport receptors (NTRs) that carry cargos through the NPC. At steady-state, up to ~100 NTRs are asymmetrically distributed throughout this FG-network. The heterogeneous and dynamic NTR/FG-network establishes a permeability barrier while simultaneously providing pathways for the translocation of import and export complexes of a wide range of sizes, affinities and surface properties. Multiple preferred paths through the central pore exist. However, the overlap, selectivity, and geometric and functional properties of these translocation conduits are largely unexplored due to the historical absence of technological tools to dissect these pathways with the necessary spatial and temporal resolution. To address this deficiency, a multi-color three- dimensional (3D) super-resolution fluorescence microscopy approach was developed in the last grant period that is capable of determining the position and orientation of individual functional NPCs combined with single particle trajectories of transiting cargo. This approach will be used to determine the structural and functional properties of multiple translocation conduits and the FG-network barrier. The Specific Aims are: 1) to determine the number and nature of protein translocation conduits; and 2) to determine the FG-polypeptide and NTR distributions within the FG-network. Aim 1 seeks to explore the possibility of at least three distinct translocation conduits, whether some of these consist of 8 distinct channels, and whether any are dedicated to either import or export. Aim 2 seeks to determine how the physical arrangement and properties of components of the FG- network are linked to promoting the identified translocation conduits. This work will directly address whether preferred routes through the permeability barrier provide a means to avoid the competition and clogging expected for two-way traffic through the same channel. In addition, improved super-resolution microscopy technologies and algorithms are expected to comprise a necessary toolkit for the field as well as to have broad applicability.


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 = $314,316 )
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	8	6/13/2025	NON-COMPETING CONTINUATION	$314,316
														Subtotal = $314,316

Issue Date FY: 2024 ( Subtotal = $314,499 )
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	7	7/23/2024	NON-COMPETING CONTINUATION	$314,499
														Subtotal = $314,499

Issue Date FY: 2023 ( Subtotal = $422,810 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	002	6	6/27/2023	NON-COMPETING CONTINUATION	$314,672
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	003	6	8/1/2023	SUPPLEMENT FOR EXPANSION	$108,138
2023	2022	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	001	5	6/12/2023	COMPETING CONTINUATION	$9
2023	2021	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	4	6/12/2023	NON-COMPETING CONTINUATION	-$9
														Subtotal = $422,810

Issue Date FY: 2022 ( Subtotal = $314,838 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	001	5	9/20/2022	COMPETING CONTINUATION	$314,838
2022	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	000	4	9/19/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $314,838

Issue Date FY: 2021 ( Subtotal = $297,000 )
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	001	4	2/26/2021	NON-COMPETING CONTINUATION	$29,700
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	000	4	12/16/2020	NON-COMPETING CONTINUATION	$267,300
														Subtotal = $297,000

Issue Date FY: 2020 ( Subtotal = $297,000 )
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	000	3	12/24/2019	NON-COMPETING CONTINUATION	$267,300
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	001	3	3/10/2020	NON-COMPETING CONTINUATION	$29,700
														Subtotal = $297,000

Issue Date FY: 2019 ( Subtotal = $373,886 )
2019	2019	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Biomedical Research and Research Training	001	2	8/2/2019	SUPPLEMENT FOR EXPANSION	$76,886
2019	2019	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	2	12/27/2018	NON-COMPETING CONTINUATION	$297,000
														Subtotal = $373,886

Issue Date FY: 2018 ( Subtotal = $248,966 )
2018	2018	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	1	12/8/2017	NEW	$248,966
														Subtotal = $248,966

Grand Total All Awards = $2,583,315

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Mapping Transport Pathways through Nuclear Pores using 3D Super-Resolution Microscopy

Award Number: R01GM126190

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: 01/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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