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

• 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
• 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

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.

项目摘要 血管衰老会影响所有灌注的组织和器官。衰老的血管平滑肌细胞（VSMC） 积聚在衰老血管中，衰老相关细胞因子的释放会促进慢性 炎症，动脉粥样硬化和更多衰老细胞的产生。鉴于他们的意义 对血管病理学的贡献，衰老VSMC现在被视为治疗靶点。 但是，消除，逆转或预防VSMC衰老的治疗方法就不得开发 知道驱动衰老的因素。我们实验室的新数据表明， 此过程是核白介素2受体a。我们的初步数据表明，IL-2RA本地化 静态VSMC的核，但在刺激VSMC增殖时离开细胞核。衰老 VSMC在刺激时不会分裂，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巴发生，该尾巴 包含与DNA结合和核定位置一致的一组碱性氨基酸。这个c 末端还包含两个已知的磷酸化位点。用两种不同的VSMC处理 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 假设将IL-2RA定位在细胞核上抑制增殖，并且不可逆的定位 IL-2RA到核的IL-2RA会促进衰老。该假设将通过以下目的解决： 目的I：定义IL-2RA如何影响VSMC的增殖和衰老。 AIM II：确定C 末端及其磷酸化会影响IL-2RA和VSMC衰老的细胞内定位。目的 III：确定如何保留IL-2RA在衰老VSMC的核中。这个项目的结果将 确定核IL-2RA直接影响VSMC中的衰老。这些发现将提供强大的 未来研究的理由确定核IL-2RA影响细胞分裂和 衰老，如何调节IL-2RA的运输以及IL-2RA的缺失如何影响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种调节细胞分裂和的新途径 VSMC和可能表达IL-2RA的其他细胞中的衰老。