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Mechanisms of CD8+ mediated cell non-autonomous arterial aging

Award Number: R01AG086447
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Mechanisms of CD8+ mediated cell non-autonomous arterial aging - PROJECT SUMMARY: Aging is the most predictive risk factor for cardiovascular disease. Aged arteries exhibit increased large artery stiffness and blunted endothelium dependent dilation; both of these changes occur prior to the onset of overt cardiovascular disease, such as atherosclerosis or stroke. Several lines of evidence have supported the emerging concept of cell non-autonomous aging, where signals arising from one cell type can drive the degenerative process of aging in other types of cells. Consistent with this concept, we have recently shown that T cells play a critical role in the development of age-related arterial stiffening and impairments in arteriolar endothelium dependent dilation. Despite this observation the T cell subtype(s), the mechanisms that result in T cell accumulation around the arteries and how T cells influence the cells of the artery remain unclear. We have found substantial age-related accumulation of memory CD8+ T cells making proinflammatory cytokines in the aorta and in the mesenteric vasculature. Eomesodermin (Eomes) is a transcription factor that drives many features consistent with CD8+ T cell aging. We have observed increased Eomes protein in both splenic CD8+ T cells as well as those that accumulate in the arteries with age. In addition to alterations in CD8+ phenotype, CD8+ trafficking also appears to be altered with age. CCL5 is a chemokine that is a potent T cell recruiter. Interestingly, our preliminary data indicates that CD8+ cells themselves generate CCL5, potentially initiating a feed forward cascade where CD8+ derived CCL5 recruit more T cells to the arteries driving arterial inflammation and cell non-autonomous arterial aging. In preliminary observations, we have also observed increased CD8+ proinflammatory cytokine production and increased proportions of Eomes expressing cells in CD8+ cells from older human donors, supporting translational potential. These observations lead to the hypothesis that both the memory/proinflammatory phenotype of CD8+ and altered CD8+ T cell trafficking drive cell non-autonomous arterial aging. To test this hypothesis, we will assess the phenotype of immune cells accumulating in the arteries, the phenotype of the artery, large artery stiffness and endothelium dependent dilation in arteries from a range of mouse models including: pharmacological and genetic deletion of T cell subtypes and adoptive transfer of young and old T cells to T cell deficient mice, as well as, pharmacological and genetic inhibition of CCL5 signaling and adoptive transfer of CCL5 deficient T cells. We will also determine whether Eomes and CCL5 signaling is associated with impaired endothelium dependent dilation and arterial stiffness in older adults. Lastly, we will employ cell culture models to determine whether CD8+ T cells from older adults can directly induce cellular changes consistent with fibrosis and endothelial dysfunction. The results of these studies will provide translational and mechanistic insight into the role of aged CD8+ T cell in cell non- autonomous arterial aging and identify targets for intervention to preserve health with age.


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 = $512,849 )
2026	2026	UNIVERSITY OF TEXAS AT ARLINGTON	701 S NEDDERMAN DR	ARLINGTON	TX	76019	TARRANT	USA	Aging Research	000	3	1/26/2026	NON-COMPETING CONTINUATION	$512,849
														Subtotal = $512,849

Issue Date FY: 2025 ( Subtotal = $583,537 )
2025	2025	UNIVERSITY OF TEXAS AT ARLINGTON	701 S NEDDERMAN DR	ARLINGTON	TX	76019	TARRANT	USA	Aging Research	000	2	12/24/2024	NON-COMPETING CONTINUATION	$535,902
2025	2025	UNIVERSITY OF TEXAS AT ARLINGTON	701 S NEDDERMAN DR	ARLINGTON	TX	76019	TARRANT	USA	Aging Research	001	2	7/22/2025	NON-COMPETING CONTINUATION	$47,635
														Subtotal = $583,537

Issue Date FY: 2024 ( Subtotal = $608,811 )
2024	2024	UNIVERSITY OF TEXAS AT ARLINGTON	701 S NEDDERMAN DR	ARLINGTON	TX	76019	TARRANT	USA	Aging Research	000	1	4/3/2024	NEW	$608,811
														Subtotal = $608,811

Grand Total All Awards = $1,705,197

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Mechanisms of CD8+ mediated cell non-autonomous arterial aging

Award Number: R01AG086447

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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