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Role of Adiposomes in Diabetes-Associated Endothelial Dysfunction and Restorative Effects of Exercise and Metabolic Surgery

Award Number: R01HL161386
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Role of Adiposomes in Diabetes-Associated Endothelial Dysfunction and Restorative Effects of Exercise and Metabolic Surgery - ABSTRACT The development of type II diabetes (T2D) is strongly associated with obesity, and both are well-established risk factors for cardiovascular disease. Vascular dysfunction is an early event in developing cardiovascular disease in obese diabetic (OB-T2D) patients. Therefore, we set our long-term goal to define molecular mechanisms of vascular dysfunction and corrective strategies that target these mechanisms, such as physical activity and weight loss. We recently discovered that human adipose tissues release extracellular vesicles (adiposomes) that are efficiently captured by endothelial cells. Adiposomes are known to carry bioactive cargos such as proteins and micro RNAs; however, their lipid content has not been studied, neither their ability to transfer their lipid cargo to endothelial cells. In the current application, we propose investigating the role of adiposomes in communicating the unhealthy milieu, mainly dysregulated lipids, to endothelial cells in OB-T2D subjects. On top of these lipid species that we propose to be carried by adiposomes are glycosphingolipids (GSLs). GSLs originate from ceramide glycosylation, a chemical process that is upregulated in the presence of inflammation and high glucose levels. Our preliminary findings showed that in endothelial cells, GSL-rich adiposomes disturb plasma membrane structure and subsequently induces endothelial dysfunction. Moreover, we found preconditioning endothelial cells with high shear stress (which is an exercise mimetic) protected endothelial cells from the detrimental effects caused by adiposomes. Therefore, our central hypothesis is that adipose tissues in OB-T2D patients release GSL-loaded adiposomes that induce vascular endothelial dysfunction. We propose that exercise and weight loss interventions (bariatric surgery) will restore adipose tissue homeostasis, reduce GSL-loaded adiposomes, and subsequently alleviate vascular risk in OB-T2D patients. We will test our hypotheses by pursuing the following Aims: Aim 1: Investigate the role of GSL-rich adiposomes in the pathogenesis of endothelial dysfunction in OB- T2D adults; Aim 2: Test the effectiveness of exercise training in reducing adiposome-mediated effects on vascular function; and Aim 3: Examine changes in adiposome/caveolae axis following metabolic surgery and their association with vascular function. This study will improve our mechanistic understanding of the biological underpinning of adiposome production, packaging, and role in inducing ED under conditions of obesity and T2D. It will also identify adiposomes and the proposed mechanisms of their interaction with endothelial cells as novel therapeutic targets for improving vascular function in OB-T2D individuals. Once these pathways are elucidated, strategies for targeting them can be advanced, leading to an improved therapeutic management of T2D-related cardiovascular disease.


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 = $639,099 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	4	12/13/2024	NON-COMPETING CONTINUATION	$639,099
														Subtotal = $639,099

Issue Date FY: 2024 ( Subtotal = $712,972 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	001	3	6/15/2024	NON-COMPETING CONTINUATION	$58,201
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	3	12/14/2023	NON-COMPETING CONTINUATION	$654,771
														Subtotal = $712,972

Issue Date FY: 2023 ( Subtotal = $743,908 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	001	2	2/17/2023	NON-COMPETING CONTINUATION	$74,391
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	2	12/20/2022	NON-COMPETING CONTINUATION	$669,517
														Subtotal = $743,908

Issue Date FY: 2022 ( Subtotal = $761,655 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	1	11/26/2021	NEW	$761,655
														Subtotal = $761,655

Grand Total All Awards = $2,857,634

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Role of Adiposomes in Diabetes-Associated Endothelial Dysfunction and Restorative Effects of Exercise and Metabolic Surgery

Award Number: R01HL161386

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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