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Spatial determinants in lipid metabolic organization at the sub-organelle level

Award Number: R35GM119768
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: 08/01/2016
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Spatial determinants in lipid metabolic organization at the sub-organelle level - Project Summary/Abstract To adapt to metabolic cues and survive stresses like nutrient starvation, cells store high- energy lipids in specialized organelles called lipid droplets (LDs) that emerge from the endoplasmic reticulum (ER), the metabolic center of cells. Recent studies reveal that LDs serve many roles in cell physiology, but how they are functionally ear-marked for specific tasks is unclear. Indeed, the ER network itself executes numerous cellular functions, but how this functional diversity is mechanistically achieved is unclear. The purpose of this grant is to dissect the molecular mechanisms by which LDs and the ER network achieve functional diversity at the sub-organelle level. Capitalizing on published and preliminary data, we find that LDs exhibit unique surface proteomes that provide functional specificity for LDs within single cells. Furthermore, we find that inter-organelle contact sites define ER sub-domains with specific roles in the compartmentalization of mevalonate metabolism. Here, I outline three directions that enable the mechanistic dissection of LD and ER functional compartmentalization: 1) In direction 1, we will leverage yeast genetics, biochemistry, and metabolic dissection to dissect how yeast ER-lysosome contacts (called nucleus-vacuole junctions, NVJs) serve as ER sub-domains and “metabolic platforms” that spatially compartmentalize mevalonate metabolism, and promote metabolic remodeling during glucose starvation. 2) In direction 2, we will capitalize on a large-scale screen to dissect how LDs are labeled with specific proteins to enable unique roles within cells. 3) In direction 3, we will utilize state-of-the-art cryo-FIB-SEM imaging to dissect how lipid phase transitions within LDs selectively remodel the LD surface proteome, and ultimately influence LD function and LD inter-organelle contact sites. Collectively, these directions will provide insights into new cellular organizational principles that enable to LDs and the ER network to achieve a functional division-of- labor. They will also characterize lipid phase transition properties of sterols, which promote disease pathologies in obesity, heart disease, and atherosclerosis.


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 = $410,000 )
2026	2026	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	10	12/23/2025	NON-COMPETING CONTINUATION	$369,000
2026	2026	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	10	3/18/2026	NON-COMPETING CONTINUATION	$41,000
														Subtotal = $410,000

Issue Date FY: 2025 ( Subtotal = $410,000 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	9	8/13/2025	NON-COMPETING CONTINUATION	$41,000
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	9	1/10/2025	NON-COMPETING CONTINUATION	$369,000
														Subtotal = $410,000

Issue Date FY: 2024 ( Subtotal = $410,000 )
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	8	1/17/2024	NON-COMPETING CONTINUATION	$369,000
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	8	6/24/2024	NON-COMPETING CONTINUATION	$41,000
														Subtotal = $410,000

Issue Date FY: 2023 ( Subtotal = $410,000 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	7	3/29/2023	NON-COMPETING CONTINUATION	$41,000
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	7	12/19/2022	NON-COMPETING CONTINUATION	$369,000
														Subtotal = $410,000

Issue Date FY: 2022 ( Subtotal = $410,000 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	003	6	7/28/2022	COMPETING CONTINUATION	$11,816
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	6	12/27/2021	COMPETING CONTINUATION	$410,000
2022	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	002	5	7/28/2022	NON-COMPETING CONTINUATION	-$11,816
2022	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	5	12/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $410,000

Issue Date FY: 2020 ( Subtotal = $405,000 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	5	7/29/2020	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2019 ( Subtotal = $405,000 )
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	4	8/12/2019	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2018 ( Subtotal = $405,000 )
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	3	7/23/2018	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2017 ( Subtotal = $405,000 )
2017	2017	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	2	8/1/2017	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2016 ( Subtotal = $404,896 )
2016	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	1	7/29/2016	NEW	$404,896
														Subtotal = $404,896

Grand Total All Awards = $4,074,896

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Spatial determinants in lipid metabolic organization at the sub-organelle level

Award Number: R35GM119768

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: 08/01/2016

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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