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

核IL-2Ra在调节血管平滑肌细胞衰老中的作用

基本信息

批准号：
10226641
负责人：
Lucile E Wrenshall
金额：
$ 7.5万
依托单位：
WRIGHT STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226641
关键词：
Address Affect Aging Alanine Amino Acids Arteries Aspartic Acid Atherosclerosis Basic Amino Acids Biological Assay Blood Vessels C-terminal Cardiovascular Diseases Cardiovascular system Cell Aging Cell Nucleus Cell division Cells Cellular biology Cessation of life Characteristics Chemicals Chronic Cytoplasmic Tail DNA Binding Data Development Disease Exhibits FRAP1 gene Future Generations Genetic Human IL8 gene Immunofluorescence Immunologic Inflammation Inflammation Mediators Interleukin 2 Receptor Interleukin-6 Interphase Cell Knock-in Knock-out Laboratories Lymphocyte Metabolic Monitor Nuclear Organ Pathology Pathway interactions Phosphorylation Phosphorylation Site Pilot Projects Prevalence Process Proliferating Protein Dephosphorylation Protein Phosphatase 2A Regulatory Subunit PR53 Public Health Regulation Reporting Resistance Role Serine Signal Transduction Smooth Muscle Myocytes Structure Tail Testing Tissues United States Vascular Smooth Muscle Western Blotting Wild Type Mouse base cell growth cytokine in vivo phosphatase inhibitor prevent senescence therapeutic target vascular smooth muscle cell proliferation

项目摘要

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.

项目总结