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Molecular regulation of endosome fission during endocytic recycling

Award Number: R01GM135326
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: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Molecular regulation of endosome fission during endocytic recycling - PROJECT SUMMARY: Recycling endosomes, organelles intimately involved in the return of proteins and lipids to the plasma membrane after their endocytosis, are of fundamental importance to plasma membrane turnover and the control of plasma membrane composition. Advancing mechanistic understanding of recycling endosome formation and function thus holds broad relevance to many areas of biomedicine. The mechanisms that regulate recycling endosome biogenesis and function remain relatively poorly understood, lagging well behind our understanding of other trafficking pathways. Our studies take advantage of the enormous technical advantages in the simple animal model C. elegans that yield mechanistic insight into cell biological processes within the physiologically relevant context of an intact metazoan animal. We then extend these find ings to mammalian cells to expand understanding and define phylogenetic conservation. We focus on a system that we pioneered, the C. e/egans intestine, a simple model that allows facile analysis of endocytic membrane transport pathways within intact polarized epithelia. There is no cell division or cell replacement in the intestine after embryogenesis, further simplifying analysis of mutant phenotypes. During the previous granting period we greatly expanded our understanding of the essential endosomal regulator RME-8/DNAJC13. Our work elucidated autoregulatory mechanisms controlling the RME-8 protein that allow RME-8 to regulate the dynamics of endosomal coats and maintain separation of endosomal microdomains with conflicting functions. We also showed that RME-8 is required for autophagic lysosome reformation in C. elegans and mouse neurons, relevant to links between RME-8 to Parkinsonism. Our new studies during the last funding period also focused our attention on fundamental forces that drive endosomal fission, particularly of recycling tubules that must be severed from sorting endosomes to form recycling endosomes. Actin polymerization on endosomes has long been proposed to provide necessary membrane tension to promote fission, but a clear understanding of how actin contributes to tension, and how fission is regulated remain as large gaps in understanding that require more in-depth study. Our studies provided surprising new evidence that non-muscle myosin II (NMII) regulates endocytic recycling. We further discovered an endosomal signaling hub centered on the Syndapin protein that controls endosomal RhoA and actomyosin. Here we propose extensive studies in C. elegans to better define how the Syndapin pathway controls NMII and fission, extend this analysis into mammalian cells, and determine the role of specific NMII isoforms in the fission process. We also identified a connection of Syndapin-based RhoA-regulation that indicates signaling from endosomes to the nucleus for long-term regulation of recycling. Our studies will test key predictions of these models and gain new understanding of mechanisms that integrate acute and long-term regulation of endocytic recycling.


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 = $347,288 )
2026	2026	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	7	7/10/2026	NON-COMPETING CONTINUATION	$347,288
														Subtotal = $347,288

Issue Date FY: 2025 ( Subtotal = $347,426 )
2025	2025	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	6	8/4/2025	NON-COMPETING CONTINUATION	$347,426
2025	2023	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	4/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $347,426

Issue Date FY: 2024 ( Subtotal = $411,227 )
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	5	8/27/2024	COMPETING CONTINUATION	$411,227
2024	2023	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	8/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $411,227

Issue Date FY: 2023 ( Subtotal = $337,907 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	4	4/13/2023	NON-COMPETING CONTINUATION	$33,790
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	1/6/2023	NON-COMPETING CONTINUATION	$304,117
														Subtotal = $337,907

Issue Date FY: 2022 ( Subtotal = $337,907 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	3	7/26/2022	NON-COMPETING CONTINUATION	$33,795
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	3	2/4/2022	NON-COMPETING CONTINUATION	$304,112
														Subtotal = $337,907

Issue Date FY: 2021 ( Subtotal = $417,026 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	2	3/16/2021	NON-COMPETING CONTINUATION	$33,706
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	1/26/2021	NON-COMPETING CONTINUATION	$303,348
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	002	2	8/24/2021	SUPPLEMENT FOR EXPANSION	$79,972
														Subtotal = $417,026

Issue Date FY: 2020 ( Subtotal = $383,917 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	1/31/2020	NEW	$383,917
														Subtotal = $383,917

Grand Total All Awards = $2,582,698

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Molecular regulation of endosome fission during endocytic recycling

Award Number: R01GM135326

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: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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