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.

项目概要血管老化影响所有灌注的组织和器官。衰老的血管平滑肌细胞（VSMC）累积在老化血管中，其中释放与衰老相关的细胞因子，促进慢性炎症、动脉粥样硬化和更多衰老细胞的产生。鉴于他们的重要由于对血管病理学的贡献，衰老的 VSMC 现在被视为治疗靶点。然而，如果不进行治疗，就无法开发出消除、逆转或预防 VSMC 衰老的治疗方法。了解导致衰老的因素。我们实验室的新数据表明，一个关键因素这个过程是核白细胞介素2受体a。我们的初步数据表明 IL-2Ra 定位于静态VSMC的细胞核，但当VSMC受到刺激增殖时离开细胞核。衰老 VSMC 在受刺激时不分裂，但在培养时继续在细胞核中表达 IL-2Ra 在增殖条件下。 IL-2Ra 的核定位可能通过细胞质尾发生，这含有与 DNA 结合和核定位一致的碱性氨基酸簇。这个C 末端尾部还含有两个已知的磷酸化位点。两种不同的方法治疗VSMC 磷酸酶抑制剂显着增加了 IL-2Ra 的核定位。基于这些发现，我们假设 IL-2Ra 定位到细胞核抑制增殖，并且不可逆定位 IL-2Ra 进入细胞核可促进衰老。该假设将通过以下目标来解决：目标 I：定义 IL-2Ra 如何影响 VSMC 增殖和衰老。目标 II：确定 C 如何末端及其磷酸化影响 IL-2Ra 和 VSMC 衰老的细胞内定位。目的 III: 确定 IL-2Ra 如何保留在衰老 VSMC 的细胞核中。该项目的结果将确定核 IL-2Ra 直接影响 VSMC 的衰老。这些发现将提供强有力的未来研究确定核 IL-2Ra 影响细胞分裂的机制的基本原理衰老、IL-2Ra 转运如何调节以及 IL-2Ra 缺失如何影响 VSMC 生物学和体内病理学。总的来说，这些未来的研究将定义一条调节细胞分裂和 VSMC 和其他可能表达 IL-2Ra 的细胞的衰老。