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Mechanisms of lipid droplet organization and functional diversification

Award Number: R01DK126887
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/03/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2030

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Mechanisms of lipid droplet organization and functional diversification - PROJECT SUMMARY/ABSTRACT Tissues store excess lipids in cytoplasmic organelles termed lipid droplets (LDs) that are critical to cellular and organismal homeostasis. Whereas long-term lipid storage occurs in adipose tissues, the liver and kidney store lipids for shorter time-periods and must actively sense, compartmentalize, or secrete lipids or lipid signaling molecules to maintain human health. Defects in this lipid balance promote diseases including fatty liver disease and type 2 diabetes (T2D), and can aggravate acute kidney injury (AKI) that affects millions of Americans and is highly prevalent in hospital patients, especially diabetics1-5. To maintain lipid homeostasis, the liver and kidney must balance the storage of absorbed lipids from blood circulation (often called “old fat” since it is made elsewhere in the body) with locally produced lipids via de novo lipogenesis (termed “new fat”). Studies reveal “old” and “new” lipid pools play distinct roles in tissue physiology and disease6-11, but a pervasive question is how these lipid pools are sensed, functionally compartmentalized, and facilitate inter-organ signaling in human health and diseases. Here, we lead a multi-disciplinary team to dissect how liver-like and kidney tissues organize their lipid pools, and how these pools are sensed and signal to execute metabolic homeostasis and tissue repair. Capitalizing on a uniquely enabling genetic screening platform we developed in Drosophila during our previous funding period, we identify genes and pathways that compartmentalize “old” and “new” lipid pools into functionally distinct LD populations in the Drosophila fat body. Through this genetic platform we discover a novel cytokine termed cDIP. Human cDIP homologs are linked to diabetes through poorly defined mechanisms22-24. We find cDIP signaling is triggered by depletion of de novo lipogenesis lipids, and influences energy signaling and inter- organ crosstalk necessary for survival. In Aims 1 and 2, we capitalize on this cDIP-dependent pathway to mechanistically dissect how lipid pools are sensed and drive inter-organ signaling and metabolic adaptation. Capitalizing on our Drosophila findings, in Aim 3 we apply these principles to the mouse kidney to address a key knowledge gap in kidney injury and repair. Following ischemia reperfusion injury (IRI) induced AKI, kidney cells accumulate LDs, but whether these are a manifestation of pathology or pro-survival is unclear. We isolate IRI-induced LDs and discover specialized LDs decorated with proteins that drive arachidonic acid metabolism and the synthesis of eicosanoids, key lipid signaling molecules mediating tissue inflammation and repair. Injury-induced LDs are also loaded with oxidation-prone linoleic acid, and we provide evidence that LDs store these lipids to suppress lipid peroxidation-associated stress. We test the innovative hypothesis that IRI- induced LDs are thus functionally specialized to coordinate eicosanoid lipid signaling and storage of oxidation- prone lipids, promoting kidney health. Collectively, our work provides new mechanistic insights into how lipid pools are sensed and organized, and how lipids signal, highly relevant to liver and kidney 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 = $777,108 )
2026	2026	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/17/2026	COMPETING CONTINUATION	$777,108
														Subtotal = $777,108

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $393,600 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/17/2024	NON-COMPETING CONTINUATION	$24,600
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/30/2023	NON-COMPETING CONTINUATION	$369,000
														Subtotal = $393,600

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	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	2/2/2023	NON-COMPETING CONTINUATION	$41,000
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/30/2022	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	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/28/2022	NON-COMPETING CONTINUATION	$41,000
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/11/2021	NON-COMPETING CONTINUATION	$369,000
														Subtotal = $410,000

Issue Date FY: 2021 ( Subtotal = $409,063 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/3/2020	NEW	$409,063
														Subtotal = $409,063

Grand Total All Awards = $2,399,771

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Mechanisms of lipid droplet organization and functional diversification

Award Number: R01DK126887

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/03/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2030

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