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Roles of Recycling Endosomes in Neuronal Extracellular Vesicle Cargo Traffic

Award Number: R01NS103967
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Roles of Recycling Endosomes in Neuronal Extracellular Vesicle Cargo Traffic - PROJECT SUMMARY The goal of this proposal is to understand how cellular membrane trafficking machinery controls the packaging and release of extracellular vesicle (EV) cargoes from synapses in vivo. EVs are small membrane-bound vesicles released by numerous cell types, including neurons, carrying cargoes critical for signaling and disease. However, we understand very little about how EV cargo traffic is spatially and temporally regulated within the polarized and complex morphology of neurons. We have developed tools to track and manipulate EV traffic at Drosophila presynaptic terminals in vivo, and discovered that flux of cargoes through a plasma membrane-recycling endosome route determines whether they are locally sorted for packaging and release in EVs, rather than depleted from synapses by retrograde transport. Recycling endosomes have primarily been studied in non-neuronal cells, and very little is known about their lifetime, functions, or dynamics at presynaptic terminals. We do know that recycling endosomes play critical roles in signaling, neuronal morphogenesis, EV traffic, and synaptic transmission. Understanding and therapeutically intervening in these important processes will require a deeper knowledge of the mechanisms of neuronal recycling endosome function. In this proposal, we will elucidate the mechanisms of synaptic EV cargo and recycling endosome traffic in vivo. To achieve these goals, we will use Drosophila genetics, biochemistry, high-resolution microscopy, and live cell imaging. 1) We will determine the functions, dynamics, and regulation of different types of synaptic recycling endosomes. To this end, we will develop new tools and approaches to define and control functionally distinct recycling compartments at synapses. Using these tools, we will test novel mechanistic hypotheses for how membrane traffic machinery sorts cargoes at synaptic recycling compartments. 2) We will determine how EV cargo traffic depends on distinct modes of synaptic endocytosis: clathrin-mediated endocytosis, which operates under low neuronal activity and activity-dependent bulk endocytosis, which operates during intense neuronal activity. These experiments will ascertain if EV fate is determined by different modes of internalization, how recycling endosomes contribute to these functions, and provide new mechanisms to link activity, endosomal traffic, and EV release. Given the conserved nature of synaptic membrane trafficking machinery, our findings and tools will lay the foundation for new insights into EV traffic in many aspects of nervous system function, including in human neurological disease.


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 = $478,251 )
2026	2026	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	12/15/2025	NON-COMPETING CONTINUATION	$430,428
2026	2026	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	2/26/2026	NON-COMPETING CONTINUATION	$47,823
														Subtotal = $478,251

Issue Date FY: 2025 ( Subtotal = $503,933 )
2025	2025	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	12/13/2024	SUPPLEMENT FOR EXPANSION	-$66,269
2025	2025	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	12/2/2024	SUPPLEMENT FOR EXPANSION	$66,269
2025	2025	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	8	1/24/2025	SUPPLEMENT FOR EXPANSION	$73,505
2025	2025	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	11/29/2024	NON-COMPETING CONTINUATION	$430,428
2025	2022	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	1/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $503,933

Issue Date FY: 2024 ( Subtotal = $596,441 )
2024	2024	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	11/30/2023	NON-COMPETING CONTINUATION	$430,428
2024	2024	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	4/15/2024	NON-COMPETING CONTINUATION	$33,475
2024	2024	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	12/5/2023	SUPPLEMENT FOR EXPANSION	$132,538
														Subtotal = $596,441

Issue Date FY: 2023 ( Subtotal = $541,103 )
2023	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	11/15/2022	COMPETING CONTINUATION	$474,834
2023	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	4/24/2023	SUPPLEMENT FOR EXPANSION	$66,269
														Subtotal = $541,103

Issue Date FY: 2022 ( Subtotal = $353,787 )
2022	2022	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	3/21/2022	NON-COMPETING CONTINUATION	$35,379
2022	2022	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/8/2021	NON-COMPETING CONTINUATION	$318,408
														Subtotal = $353,787

Issue Date FY: 2021 ( Subtotal = $353,820 )
2021	2021	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/30/2020	NON-COMPETING CONTINUATION	$318,438
2021	2021	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/19/2021	NON-COMPETING CONTINUATION	$35,382
														Subtotal = $353,820

Issue Date FY: 2020 ( Subtotal = $353,853 )
2020	2020	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/12/2020	NON-COMPETING CONTINUATION	$35,386
2020	2020	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/27/2019	NON-COMPETING CONTINUATION	$318,467
														Subtotal = $353,853

Issue Date FY: 2019 ( Subtotal = $355,469 )
2019	2019	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/28/2018	NON-COMPETING CONTINUATION	$355,469
														Subtotal = $355,469

Issue Date FY: 2018 ( Subtotal = $871,227 )
2018	2018	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	9/19/2018	SUPPLEMENT FOR EXPANSION	$162,250
2018	2018	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/8/2017	NEW	$355,469
2018	2018	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/14/2018	SUPPLEMENT FOR EXPANSION	$353,508
														Subtotal = $871,227

Grand Total All Awards = $4,407,884

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Roles of Recycling Endosomes in Neuronal Extracellular Vesicle Cargo Traffic

Award Number: R01NS103967

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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