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Role of nuclear IL-2Ra in regulation of vascular smooth muscle cell senescence

Award Number: R03AG068696
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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Role of nuclear IL-2Ra in regulation of vascular smooth muscle cell senescence - Project Summary Vascular aging impacts all perfused tissues and organs. Senescent vascular smooth muscle cells (VSMC) accumulate in aging vessels, where the release of senescence-associated cytokines promotes chronic inflammation, atherosclerosis, and the generation of more senescent cells. Given their significant contributions to vascular pathology, senescent VSMC are now being viewed as a therapeutic target. However, treatments to eliminate, reverse, or prevent VSMC senescence cannot be developed without knowing the factors that drive senescence. New data from our laboratory suggests that one key factor in this process is nuclear interleukin 2 receptor a. Our preliminary data show that IL-2Ra localizes to the nucleus of quiescent VSMC but leaves the nucleus when VSMC are stimulated to proliferate. Senescent VSMC, which do not divide when stimulated, continue to express IL-2Ra in the nucleus when cultured under proliferative conditions. Nuclear localization of IL-2Ra may occur through the cytoplasmic tail, which contains a cluster of basic amino acids consistent with DNA binding and nuclear localization. This C terminal tail also contains two known phosphorylation sites. Treatment of VSMC with two different phosphatase inhibitors significantly increased nuclear localization of IL-2Ra. Based on these findings, we hypothesize that localization of IL-2Ra to the nucleus inhibits proliferation, and that irreversible localization of IL-2Ra to the nucleus promotes senescence. This hypothesis will be addressed by the following aims: Aim I: Define how IL-2Ra impacts VSMC proliferation and senescence. Aim II: Determine how the C terminus, and its phosphorylation, impacts intracellular localization of IL-2Ra and VSMC senescence. Aim III: Determine how IL-2Ra is retained in the nucleus of senescent VSMC. Results from this project will establish that nuclear IL-2Ra directly impacts senescence in VSMC. These findings will provide a strong rationale for future studies determining the mechanism by which nuclear IL-2Ra impacts cell division and senescence, how transport of IL-2Ra is regulated, and how the absence of IL-2Ra affects VSMC biology and pathology in vivo. In total, these future studies will define a new pathway for regulating cell division and senescence in VSMC and potentially other cells expressing IL-2Ra.


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: 2024 ( Subtotal = $0 )
2024	2022	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Aging Research	000	2	7/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $75,000 )
2022	2022	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Aging Research	001	2	6/9/2022	NON-COMPETING CONTINUATION	$7,500
2022	2022	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Aging Research	000	2	2/24/2022	NON-COMPETING CONTINUATION	$67,500
														Subtotal = $75,000

Issue Date FY: 2021 ( Subtotal = $75,000 )
2021	2021	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Aging Research	000	1	4/29/2021	NEW	$75,000
														Subtotal = $75,000

Grand Total All Awards = $150,000

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Role of nuclear IL-2Ra in regulation of vascular smooth muscle cell senescence

Award Number: R03AG068696

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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