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Molecular mechanisms of exocytotic vesicle fusion and release.

Award Number: R35GM139608
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: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Molecular mechanisms of exocytotic vesicle fusion and release. - Fusion of membrane bound vesicles with a target membrane is of ubiquitous importance for cellular function from intracellular trafficking to exocytotic release of various mediators from a wide range of different cell types. The mechanisms of exocytosis and their regulation are the central topic of the research program in my laboratory. Exocytotic release occurs from the interior of secretory vesicles to the outside of the cell via formation of a fusion pore. The SNARE (Soluble NSF Attachment REceptor) complex, which in mammalian neurons and neuroendocrine cells is composed of the proteins synaptobrevin-2, syntaxin-1, and SNAP-25, plays a key role in vesicle fusion. My laboratory has investigated vesicle fusion mechanisms in mast cells, which release histamine and heparin; in neutrophils, which are part of the innate immune system and release antimicrobial proteins; and in eosinophils, which release cytotoxic proteins to combat parasites. At present we are mostly focused on the investigation of the exocytotic fusion mechanism in chromaffin cells, which we have chosen for their specific advantages for experimental approaches and because their neuronal molecular fusion machinery is better known than those of other cell types. Over the next 5 years, the function of the neuronal SNARE proteins synaptobrevin2, syntaxin 1, SNAP25, and the accessory proteins synaptotagmin, complexin, Munc18 and Munc13 in vesicle fusion and priming will be investigated as a model system to understand the general mechanisms vesicle docking, priming and fusion. For these studies we will combine highly innovative experimental and computational approaches developed in my laboratory to elucidate the nanomechanical motions and interactions that lead to vesicle fusion and exocytotic release. Event Correlation Microscopy using microfabricated Electrochemical Detector Arrays will be used to experimentally interrogate specific molecular interactions and conformational changes related to fusion pore formation in cells and reconstituted systems. The experimental research will be complemented by molecular dynamics simulations to interpret the experimental data and to guide the experimental design. Various crystal structures of parts of the machinery have been determined, which provide very high atomistic resolution, but they represent static structures. To understand the functions of these protein complexes, their dynamic structural changes need to be elucidated. The long term goal of my research is to achieve a true understanding of the nanomechanical mechanisms of vesicle fusion docking, priming, fusion, and release. Our ultimately vision is to obtain realistic molecular movies of the actions of fusion machine, providing deep insight into the mechanisms of vesicle priming and fusion pore formation. This research will also advance our understanding of the related intracellular trafficking fusion events as well as viral entry, which employ closely related fusion mechanisms. .


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 = -$1,939 )
2026	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Biomedical Research and Research Training	000	6	6/11/2026	NON-COMPETING CONTINUATION	-$1,939
														Subtotal = -$1,939

Issue Date FY: 2025 ( Subtotal = $383,750 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Biomedical Research and Research Training	002	6	8/13/2025	NON-COMPETING CONTINUATION	$38,375
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Biomedical Research and Research Training	001	6	12/12/2024	NON-COMPETING CONTINUATION	$345,375
2025	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Biomedical Research and Research Training	000	5	11/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $383,750

Issue Date FY: 2024 ( Subtotal = $383,750 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Biomedical Research and Research Training	000	5	1/4/2024	NON-COMPETING CONTINUATION	$345,375
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Biomedical Research and Research Training	001	5	6/24/2024	NON-COMPETING CONTINUATION	$38,375
														Subtotal = $383,750

Issue Date FY: 2023 ( Subtotal = $383,750 )
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Biomedical Research and Research Training	001	4	3/24/2023	NON-COMPETING CONTINUATION	$38,375
2023	2023	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Biomedical Research and Research Training	000	4	12/16/2022	NON-COMPETING CONTINUATION	$345,375
														Subtotal = $383,750

Issue Date FY: 2022 ( Subtotal = $364,199 )
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Biomedical Research and Research Training	002	3	1/21/2022	NON-COMPETING CONTINUATION	$345,375
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Biomedical Research and Research Training	003	3	7/20/2022	NON-COMPETING CONTINUATION	$38,375
2022	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	004	1	7/26/2022	NEW	-$1
2022	2021	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Biomedical Research and Research Training	001	2	12/21/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$285,811
2022	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	1	12/21/2021	NEW	-$305,361
														Subtotal = $364,199

Issue Date FY: 2021 ( Subtotal = $410,000 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	1	12/3/2020	NEW	$410,000
														Subtotal = $410,000

Grand Total All Awards = $1,923,510

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Molecular mechanisms of exocytotic vesicle fusion and release.

Award Number: R35GM139608

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: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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