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Cargo Transport by Myosin Va and Kinesin-1 Molecular Motors: In Vitro Model Systems that Build Complexity in 3-Dimensions.

Award Number: R35GM141743
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Intracellular cargo transport, such as lipid-bound insulin granules and presynaptic vesicles that are destined for secretion at the plasma membrane, rely on the concerted effort of kinesin-1 (kin1) and myosin Va (myoVa) molecular motors. These double-headed molecular motors carry their common cargo by stepping processively for considerable distances along their respective cytoskeletal tracks, i.e. microtubules (MTs) for kin1 and actin filaments for myoVa. To successfully deliver cargo, teams of kin1 and myoVa motors on the cargo surface, must overcome the physical challenges presented by the 3-dimensional (3D) complex network of MTs and actin filaments that comprise the cell’s cytoskeleton, which also serves as these motors’ highways. To determine how efficient intracellular cargo transport and delivery are accomplished despite the physical challenges presented by the cell’s complex cytoskeletal highway, we have developed a near-physiological in vitro model system of kin1 and myoVa transport that is composed of a complex, but well-defined, 3- dimensional (3D), MT and actin filament network. Physiologically-relevant lipid-bound liposomes will be formed having Rab receptor proteins embedded in the liposome membranes so that molecular motors can be linked to the Rab receptors through their respective adapter proteins as in vivo. Once formed, motor-coated liposomes are introduced into the 3D networks and their transport trajectories defined using state-of-the-art single molecule biophysical techniques with high spatial and temporal resolution. Track-binding proteins to MTs (MAP7, Tau) and actin filaments (tropomyosins) will be added to dictate the direction of liposome transport. Key questions to be addressed using this well-defined model system are: 1) How are motors loaded onto the cargo surface? 2) Are motors on the cargo surface that are not engaged in transport, passive hitchhikers or are they cargo tethers that electrostatically interact with the heterologous track to enhance cargo transport by the actively engaged motors? 3) Is cargo hand-off from MT- to actin-based transport a coordinated event or the result of a tug of war? 4) Do track-binding proteins help to sort cargo by enhancing or inhibiting transport on specific MT and actin filaments? To interpret the results of these experiments, we will develop a mechanistic in silico transport model that incorporates the mechanical interactions between motor teams on the liposome surface. We propose that a functional interplay exists between the properties of the cytoskeletal tracks, motors, and cargos, which determines how teams of molecular motors meet the cellular demands placed on them by 3D cytoskeletal highways. The data obtained will provide a rich, mechano-spatial knowledgebase for the field and serve as a foundation for understanding molecular motor transport in the complex cytoarchitectural environment of the cell and how efficient motor transport systems are designed for delivery and retention of cargo at its destination.


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: 2024 ( Subtotal = $380,203 )
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	000	4	4/16/2024	NON-COMPETING CONTINUATION	$380,203
														Subtotal = $380,203

Issue Date FY: 2023 ( Subtotal = $646,057 )
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	001	3	7/20/2023	SUPPLEMENT FOR EXPANSION	$223,610
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	000	3	4/27/2023	NON-COMPETING CONTINUATION	$422,447
														Subtotal = $646,057

Issue Date FY: 2022 ( Subtotal = $422,447 )
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	001	2	7/21/2022	NON-COMPETING CONTINUATION	$42,246
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	000	2	4/7/2022	NON-COMPETING CONTINUATION	$380,201
														Subtotal = $422,447

Issue Date FY: 2021 ( Subtotal = $435,724 )
2021	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	000	1	4/14/2021	NEW	$435,724
														Subtotal = $435,724

Grand Total All Awards = $1,884,431

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Cargo Transport by Myosin Va and Kinesin-1 Molecular Motors: In Vitro Model Systems that Build Complexity in 3-Dimensions.

Award Number: R35GM141743

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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