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Roles of endoplasmic reticulum subdomains in regulating intracellular lipid distribution and organelle biogenesis

Award Number: R35GM153315
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: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Roles of endoplasmic reticulum subdomains in regulating intracellular lipid distribution and organelle biogenesis - Project Summary/Abstract The endoplasmic reticulum (ER) plays a central role in many cellular processes, including lipid metabolism. The ER network is formed from a single membrane and yet contains functionally distinct subdomains that allows the ER to regulate lipid metabolism and respond to stress. How this functional diversity is mechanistically achieved is not well understood. One type of ER subdomain are regions of the ER in close contact with other organelles, called membrane contact sites (MCSs). They play important roles in cellular lipid homeostasis, signaling, and stress responses. Other subdomains are regions where some organelles are formed. One is lipid droplets (LDs), which are lipid storage depots that have many roles in cell physiology. Here, I take a multidisciplinary approach to address key gaps in our knowledge about the formation and function of ER subdomains. Central to the projects in this proposal is the question of how cells control the distribution of lipids within the ER and how this contributes to cellular lipid homeostasis. There are three directions in the proposal. 1) Direction one addresses key gaps in our understanding of how LD biogenesis occurs and goes awry in disease. We will leverage a novel in vitro LD biogenesis assay we have developed to investigate mechanism of LD formation and the roles LD biogenesis proteins. We will also determine how disease-causing mutations in these proteins alters their functions. 2) Direction two addresses the mechanism and functions of a recently described new family of tube- like lipid transport proteins that operate MCSs. 3) Direction three addresses a key gap in our knowledge of how the hydrophobic metabolite Coenzyme Q (CoQ) exits mitochondria and reaches the ER and other compartment and how export is regulated in response to oxidative stress. Capitalizing on a novel genetic screen we conducted, we will identify proteins that facilitate and regulate CoQ interorganelle transport. Collectively, these directions will provide mechanistic insights into the formation and functions of ER subdomains and how defects in these processes contribute to various 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: 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	2	4/1/2025	NON-COMPETING CONTINUATION	$410,000
2025	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	1	11/21/2024	NEW	$0
														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	1	3/5/2024	NEW	$410,000
														Subtotal = $410,000

Grand Total All Awards = $820,000

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Roles of endoplasmic reticulum subdomains in regulating intracellular lipid distribution and organelle biogenesis

Award Number: R35GM153315

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: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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