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NKA/CD36 signaling in adipocytes promotes oxidative stress and drives chronic inflammation in atherosclerosis

Award Number: R01HL164460
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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NKA/CD36 signaling in adipocytes promotes oxidative stress and drives chronic inflammation in atherosclerosis - Atherosclerosis (AS) is a chronic inflammatory disease of medium and large arteries and remains the leading cause of death worldwide from its sequelae of heart attack, stroke and limb loss. During AS progression chronic activation of immune cells in the vessel wall, especially macrophages, leads to formation of lipid-loaded foam cells which become the major component of atherosclerotic plaque. The goal is to discover molecular mechanisms through which dyslipidemia and oxidative stress, which are major risk factors for AS, are linked to chronic macrophage activation via dysregulated function of fat cells (adipocytes). The proposal will explore how adipocyte-derived exosomes (Ad-Exo) carrying specific pro-atherogenic cargo such as miRNAs, are generated under oxidative stress, and how they activate macrophages. Focus is CD36, type II scavenger receptor highly expressed in adipocytes and macrophages that acts as a receptor for the atherogenic ligand oxidized LDL (oxLDL). The oxLDL/CD36 signaling axis creates an inflammatory paracrine loop between macrophages and adipocytes and facilitates oxidative stress and pro-inflammatory cytokine secretion through Src family kinase (SFK) activation. Na/K-ATPase (NKA) α1 subunit serves both as a CD36 co- receptor and a scaffold for the SFK, allowing conformational changes in the NKA to activate membrane bound SFK and initiate signaling cascades, a mechanism distinct from its well-understood pumping function. Hypothesis of this proposal is that activation of NKA/CD36 signaling in adipocytes produces oxidative stress that causes release of adipokines and exosomes (Ad-Exo). These released factors initiate and augment AS by stimulating macrophages. To test this hypothesis, 3 specific aims have been developed. The first will test the hypothesis that adipocyte NKA/CD36 signaling complex promotes AS through production of cellular oxidative stress leading to abnormal adipokines/exosome secretion. The approach will include use of the apoe null mouse model and lentiviral vectors to deliver cell-specific NaKtide, a peptide reagent derived from the NKA α1 domain that behaves as a specific inhibitor of the NKA/SFK pathway. Oxidant stress, AS plaque formation, and adipocyte gene expression will be assessed using state-of-the-art techniques, such as next generation RNASeq. The second aim will test whether Ad-Exo can modulate macrophage function in vitro and in vivo by characterizing the proteome, lipidome and miRNA profile of Ad-Exo released in response to oxidative stress and tracking their delivery to monocytes and AS plaque. A newly developed mouse model, GFP- CD63flox/Adipoq Cre mice will be used as an excellent Ad-Exo reporter animal model for these studies. The third aim will determine if Ad-Exo regulate macrophage lipid metabolism and mitochondrial function using sophisticated metabolic flux assays along with lipidomic and gene expression assays. Successful completion of this project will define an important concept that adipocyte CD36/NKA and downstream Ad-Exo secretion is a driving force for chronic macrophage activation in AS, thereby identifying novel therapeutic targets.


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 = $480,778 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	3	3/14/2025	NON-COMPETING CONTINUATION	$480,778
														Subtotal = $480,778

Issue Date FY: 2024 ( Subtotal = $523,513 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	001	2	8/2/2024	NON-COMPETING CONTINUATION	$523,513
2024	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	1	8/1/2024	NEW	$0
														Subtotal = $523,513

Issue Date FY: 2023 ( Subtotal = $547,197 )
2023	2023	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	1	3/15/2023	NEW	$547,197
														Subtotal = $547,197

Grand Total All Awards = $1,551,488

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NKA/CD36 signaling in adipocytes promotes oxidative stress and drives chronic inflammation in atherosclerosis

Award Number: R01HL164460

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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