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Composition and Function of Membrane Contact Sites in Differentiation and Disease

Award Number: R35GM133460
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: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Composition and Function of Membrane Contact Sites in Differentiation and Disease - ABSTRACT Eukaryotic cells are compartmentalized into membrane-bound organelles to spatially separate incompatible biochemical processes. However, organelles must co-ordinate their activities so that cells can respond to changing developmental or environmental conditions. One mechanism of coordination is via membrane contact sites (MCSs), sites of close apposition between organelles used for the exchange of ions, lipids, and proteins. Despite being implicated in multiple metabolic and neurodegenerative diseases, the function and composition of many MCSs is not well understood. The proposed research program will continue to explore the function and composition of MCSs via two related themes. Because different cell types have diverse morphologies and physiological functions, we hypothesize that organelle structure and communication must remodel throughout differentiation of stem cells. In theme A, we will use multispectral imaging of organelles followed up with mechanistic studies to elucidate how and why MCSs rewire during differentiation of stem cells into neurons or skeletal muscle. This will identify common themes in organelle and MCS reorganization during differentiation, as well as features unique to each cell type. In theme B, we will focus on lipid droplet (LD)- organelle MCSs. LDs are lipid storage organelles with a unique structure consisting of a neutral lipid core surrounded by a phospholipid monolayer. The unique monolayer membrane means that LDs are not connected to vesicular trafficking pathways, so MCSs are the only way these organelles can exchange material with other organelles. We will use spatial proteomics to identify proteins at LD contacts with other organelles including mitochondria, the endoplasmic reticulum (ER), and the plasma membrane. We will then test the roles of LD-organelle MCS proteins in cellular functions including lipid and protein trafficking. These studies will yield important insights into how cells reorganize to support diverse cellular physiologies during normal development. In addition, our work will elucidate how defects in organelle communication contribute to conditions including metabolic, neurodevelopmental, and neurodegenerative diseases.


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 = $421,343 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	7	2/18/2026	NON-COMPETING CONTINUATION	$421,343
														Subtotal = $421,343

Issue Date FY: 2025 ( Subtotal = $421,331 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	6	4/14/2025	COMPETING CONTINUATION	$421,343
2025	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	5	11/26/2024	NON-COMPETING CONTINUATION	-$12
														Subtotal = $421,331

Issue Date FY: 2023 ( Subtotal = $446,998 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	5	6/2/2023	NON-COMPETING CONTINUATION	$446,998
														Subtotal = $446,998

Issue Date FY: 2022 ( Subtotal = $497,574 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	4	7/8/2022	SUPPLEMENT FOR EXPANSION	$116,694
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	4	5/4/2022	NON-COMPETING CONTINUATION	$380,880
														Subtotal = $497,574

Issue Date FY: 2021 ( Subtotal = $380,880 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	3	5/11/2021	NON-COMPETING CONTINUATION	$380,880
														Subtotal = $380,880

Issue Date FY: 2020 ( Subtotal = $380,880 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	2	5/14/2020	NON-COMPETING CONTINUATION	$380,880
														Subtotal = $380,880

Issue Date FY: 2019 ( Subtotal = $380,880 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	1	7/19/2019	NEW	$380,880
														Subtotal = $380,880

Grand Total All Awards = $2,929,886

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Composition and Function of Membrane Contact Sites in Differentiation and Disease

Award Number: R35GM133460

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: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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