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Unraveling the mechanisms behind lymphatic dysfunction in obesity: are weight-loss drugs effective at restoring lymphatic function?

Award Number: F31HL179791
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/12/2025
PERIOD OF PERFORMANCE END DATE: 08/11/2027

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Unraveling the mechanisms behind lymphatic dysfunction in obesity: are weight-loss drugs effective at restoring lymphatic function? - PROJECT SUMMARY/ABSTRACT Lymphedema is a chronic, debilitating disease affecting >250 million people worldwide with no pharmacological therapies available. Recently, it has been established that there is a reciprocal relationship between dysfunction of the lymphatic system and obesity, i.e., obesity causes lymphatic dysfunction and lymphatic dysfunction exacerbates obesity, creating a vicious cycle. Clinical studies have demonstrated that patients with obesity are at significantly higher risk of developing lymphedema; and in breast cancer patients, obesity is known to increase the chances of developing lymphedema following surgical and radiotherapeutic interventions. Therefore, there is a critical need to identify the molecular mechanisms of lymphatic dysfunction in obesity in order to develop the first pharmacological therapeutics to treat lymphedema. GLP-1 receptor (GLP-1R) agonists were originally developed and approved for the treatment of Type 2 Diabetes and recently have been shown to be effective for reducing bodyweight. However, the effects of GLP-1R drugs on the function of the lymphatic system remain unexplored. The diet-induced obese ApoE-deficient (DIO-ApoEKO) mouse is a known model to study obesity and metabolic syndrome, and it also displays various aspects of lymphatic dysfunction; however, the underlying mechanisms remain unknown. Our preliminary findings using single-cell RNA sequencing on microdissected lymphatic vessels from non-obese wild type (WT) and non-obese ApoE KO mice revealed significant differentially expressed genes across many cell types, including lymphatic endothelial cells (LECs), lymphatic muscle cells (LMCs), and tissue resident macrophages (TRMs). In LECs, several genes in the mitochondrial electron transport chain were significantly downregulated in ApoE KO mice, suggestive of mitochondrial dysfunction. LMCs from ApoE KO mice exhibited differentially expressed genes involved in contractile function – both contractile apparatus and ion channels, suggestive of a change in contractile phenotype. In control mice, Apoe expression was most abundant in TRMs. TRMs from ApoE KO mice displayed a significantly reduced expression of M2-like macrophage markers and upregulation of M1-like macrophage markers, suggesting a transition to a pro-inflammatory polarization. Therefore, to characterize transcriptomic alterations, identify novel molecular mechanisms of lymphatic dysfunction associated with obesity, and to test the hypothesis that weight-loss driven by pharmacological targeting of GLP-1R improves lymphatic function in obesity, we propose the following two independent, but synergistic aims: 1) characterize transcriptomic and functional alterations in lymphatic vessels from DIO-ApoEKO mice and 2) assess the effects of GLP-1R agonists on the function of collecting lymphatic vessels and determine the therapeutic potential of GLP-1R weight-loss drugs to improve lymphatic function in DIO-ApoEKO mice. We anticipate that these experiments will provide novel insights into the molecular mechanisms that underlie lymphatic dysfunction in diet-induced obesity and hypothesize that GLP-1R agonism with Semaglutide will improve metabolic changes in DIO-ApoEKO mice and restore lymphatic function.


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 = $50,114 )
2026	2026	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	2	8/5/2026	NON-COMPETING CONTINUATION	$50,114
														Subtotal = $50,114

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	001	1	8/12/2025	NEW	$0
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	1	8/12/2025	NEW	$49,538
														Subtotal = $49,538

Grand Total All Awards = $99,652

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Unraveling the mechanisms behind lymphatic dysfunction in obesity: are weight-loss drugs effective at restoring lymphatic function?

Award Number: F31HL179791

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/12/2025

PERIOD OF PERFORMANCE END DATE: 08/11/2027

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