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 血管老化影响所有灌注的组织和器官。衰老血管平滑肌细胞 在老化的血管中积累，其中衰老相关细胞因子的释放促进慢性炎症。 炎症、动脉粥样硬化和更多衰老细胞的产生。鉴于其重要的 由于VSMC对血管病理学的贡献，衰老的VSMC现在被视为治疗靶点。 然而，消除、逆转或预防VSMC衰老的治疗方法不能在不进行治疗的情况下开发。 了解导致衰老的因素。我们实验室的新数据表明， 这个过程是细胞核白细胞介素2受体A。我们的初步数据显示IL-2 Ra定位于 当VSMC被刺激增殖时，VSMC离开细胞核。衰老 VSMC在刺激时不分裂，在培养时继续在细胞核中表达IL-2 Ra 在增殖条件下。IL-2 Ra的核定位可能通过细胞质尾部发生，这 含有一组与DNA结合和核定位一致的碱性氨基酸。这个C 末端尾部还含有两个已知的磷酸化位点。用两种不同的药物治疗VSMC 磷酸酶抑制剂显著增加IL-2 Ra的核定位。基于这些发现，我们 假设IL-2 Ra定位于细胞核抑制增殖，且不可逆定位 IL-2 Ra对细胞核的作用促进衰老。这一假设将通过以下目标来解决： 目的I：确定IL-2 Ra如何影响VSMC增殖和衰老。目标二：确定C IL-2 R α末端及其磷酸化影响IL-2 R α的细胞内定位和VSMC衰老。目的 III：确定IL-2 Ra如何保留在衰老的VSMC的核中。该项目的成果将 证实了细胞核IL-2 Ra直接影响VSMC的衰老。这些发现将提供一个强有力的 未来研究确定核IL-2 Ra影响细胞分裂的机制的基本原理， 衰老，IL-2 Ra的转运如何调节，以及IL-2 Ra的缺乏如何影响VSMC生物学 和体内病理学。总之，这些未来的研究将确定一种新的调节细胞分裂的途径， VSMC和潜在表达IL-2 Ra的其他细胞中的衰老。