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Mechanism of cholesterol regulation by the mitochondrial translocator protein (TSPO)

Award Number: R01DK110059
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Free cholesterol is an essential structural component required for integrity and fluidity of membrane bilayers important for cell signaling and regulation of lipid metabolism. Free cholesterol is also the precursor for the synthesis of steroid hormones and bile acids. The balance between free cholesterol and its esterified storage form is tightly regulated by all cells in the body, and is crucial for preventing hypercholesterolemia and associated disorders. Until recently, it was believed that the translocator protein (TSPO) present in the outer mitochondrial membrane was a transporter for cholesterol to enter the mitochondria for steroid hormone production. We overturned this assumption in recent work demonstrating that TSPO is not involved in this process. This void has refocused attention on elucidating the role of TSPO action. This is of extreme importance because upregulation of TSPO is seen in multiple human pathologies, and there are currently 24 human clinical trials targeting TSPO for therapeutic or diagnostic purposes. By reexamining the relationship between TSPO and cholesterol using different Tspo gene deleted models we have identified a novel link between TSPO and cholesterol esterification. The objective of this application is to elucidate the precise role of TSPO: (Aim 1) Define the TSPO-mediated mechanism in cholesterol esterification, and (Aim 2) Understand the in vivo changes to lipid homeostasis in Tspo knockout (Tspo-/-) mice. The experimental plans for this project extend from molecular characterization of TSPO to studying its functional relevance using in vivo metabolism models. Using in vitro models, we investigate the importance of cholesterol binding and protein interactions to TSPO by evaluating specific amino acid mutations to putative binding sites; we also perform metabolomics to evaluate cellular responses and determine functional integration with known pathways of cholesterol regulation in cells. Using in vivo models, we examine TSPO effects on lipid metabolism in the liver and white adipose tissue and the associated impact on plasma lipids. Results from these studies are poised to offer novel insights into lipid regulation by TSPO that might explain specific pathological dysfunctions observed in atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). In addition, knowledge of TSPO function will be highly relevant to describing the basis of its involvement in pathologies and defining the principles underlying pharmacological targeting of TSPO for advancing human medicine.


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: 2023 ( Subtotal = $0 )
2023	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $333,607 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/19/2021	NON-COMPETING CONTINUATION	$333,607
														Subtotal = $333,607

Issue Date FY: 2020 ( Subtotal = $331,418 )
2020	2020	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/16/2020	NON-COMPETING CONTINUATION	$331,418
														Subtotal = $331,418

Issue Date FY: 2019 ( Subtotal = $327,711 )
2019	2019	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/2/2019	NON-COMPETING CONTINUATION	$327,711
														Subtotal = $327,711

Issue Date FY: 2018 ( Subtotal = $329,422 )
2018	2018	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/20/2018	NON-COMPETING CONTINUATION	$296,479
2018	2018	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/23/2018	NON-COMPETING CONTINUATION	$32,943
														Subtotal = $329,422

Issue Date FY: 2017 ( Subtotal = $326,158 )
2017	2017	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/3/2017	NEW	$326,158
														Subtotal = $326,158

Grand Total All Awards = $1,648,316

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Mechanism of cholesterol regulation by the mitochondrial translocator protein (TSPO)

Award Number: R01DK110059

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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