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Unraveling the cell divergent roles of Glucocorticoid-Induced TNF-R Related Protein (GITR): A new opportunity to treat atherosclerosis using targeted immunotherapy

Award Number: R01HL171097
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Unraveling the cell divergent roles of Glucocorticoid-Induced TNF-R Related Protein (GITR): A new opportunity to treat atherosclerosis using targeted immunotherapy - SUMMARY Although preclinical studies have implicated inflammation as a main driver of atherosclerotic disease for the past two decades, its clinical relevance has only been recently validated in proof-of-concept trials. Immune checkpoint proteins, including co-stimulatory and co-inhibitory proteins, are master regulators of the immune response and were originally described to allow cognate interactions between T cells and antigen presenting cells (APCs). Lately, it has become clear that immune checkpoint proteins are expressed on a plethora of immune cells, including macrophages. The sequence, the location and the extent of these interactions condition the very establishment of an immune response and its resolution or chronicity. Understanding the role of immune checkpoint proteins in CVD is crucial, as immune checkpoints exert cell-type specific actions and signaling in atherosclerosis and can therefore be targeted specifically. We have identified an important role for the co-stimulatory immune checkpoint protein Glucocorticoid Induced TNF-Related Protein (GITR) in atherosclerosis. In human atherosclerotic plaques, we found that GITR expression is associated with a vulnerable plaque phenotype. Although GITR is well-known to be expressed on T cells, our preliminary data show that macrophage GITR plays a key role in atherosclerosis. Macrophages in plaques start expressing GITR in intermediate and advanced stages of atherosclerosis and Cite-seq analysis of the mouse atherosclerotic aorta showed that GITR+CD68+ cells display the transcriptome of inflammatory macrophages. GITR-/-ApoE-/- mice display a reduction in atherosclerosis and develop a stable plaque phenotype, due to a reduction of monocyte recruitment and macrophage activation. Deficiency of GITR did not affect regulatory or effector T cells. Likewise, LysM-GITRflflApoE-/- mice, but not CD4-GITRflflApoE-/- mice, develop less atherosclerosis. Deficiency of GITR on macrophages reduces their migration, TNF production, ROS levels and mitochondrial stress. Elevated plasma levels of sGITR, which we found to be released by macrophages and not T cells, are associated with the presence of CVD. We hypothesize that GITR-signaling in macrophages drives atherosclerosis, and that targeting (macrophage) GITR is a safe immunotherapeutic approach that will ameliorate ASCVD, as GITR deficiency affects macrophage biology, but not T cell function. We propose to unlock GITR’s full translational potential as biomarker and immunotherapeutic target for atherosclerosis. In aim 1, we will detail GITR’s macrophage specific effects and mechanisms in atherosclerosis. In aim 2, we will test the translational potential of our newly designed GITR inhibitors using a systemic and macrophage targeted nanobiologic approach. In aim 3, we will test the potential of sGITR as biomarker for CVD. Knowledge on cell-type specific actions of immune checkpoints warrants cell targeted immune checkpoint- based therapeutics that attenuate atherosclerosis-specific inflammatory pathways and will cause limited immune-related side effects, an essentiality to render immunotherapy a relevant treatment modality for CVD.


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 = $712,785 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	001	2	3/27/2026	NON-COMPETING CONTINUATION	$21,820
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	000	2	2/16/2026	NON-COMPETING CONTINUATION	$690,965
														Subtotal = $712,785

Issue Date FY: 2025 ( Subtotal = $709,869 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	000	1	12/13/2024	NEW	$709,869
														Subtotal = $709,869

Grand Total All Awards = $1,422,654

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Unraveling the cell divergent roles of Glucocorticoid-Induced TNF-R Related Protein (GITR): A new opportunity to treat atherosclerosis using targeted immunotherapy

Award Number: R01HL171097

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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