Role of HDAC7 in senescence-associated inflammation

项目摘要 细胞衰老是衰老过程的标志，并导致慢性疾病的脆弱性。 虽然衰老作为一种肿瘤抑制机制急性，慢性它也有助于 通过衰老相关分泌表型（SASP）的衰老组织炎症。因此， 体内衰老细胞的减少可以改善健康和寿命，尽管药理学上的“衰老清除”方法 往往具有毒副作用，可能限制了senolytics作为促进健康衰老的工具的效用。作为 另一种方法的概念验证，体内抑制SASP可减少慢性肝脏炎症 并延迟肝细胞癌的发病。最近，我们已经表明，SASP是依赖于驱逐 细胞质染色质碎片（CCF）从细胞核进入细胞质的衰老细胞。我们有 最近通过逆行线粒体信号传导将线粒体功能障碍与CCF产生联系起来， 通路该途径被组蛋白去乙酰化酶抑制剂通过未知的机制阻断。 出乎意料的是，我们最近发现组蛋白去乙酰化酶HDAC7定位于衰老的细胞核中， 是CCF形成所必需的，并且对线粒体状态敏感。我们假设HDAC7是一种 衰老细胞中的视神经核逆行信号的新组分。该提案有两个 目的：1）确定HDAC7的线粒体信号传导作用，2）确定HDAC7的核作用， CCF形成中的HDAC7。阐明这一信号通路的机制是所有人感兴趣的 生物学家，但也可以确定减少SASP的治疗靶点。这种方法可以揭示 用于治疗与年龄相关的疾病和促进健康老龄化的衰老药物的替代品。

PROJECT SUMMARY Cellular senescence is a hallmark of the aging process and contributes to chronic disease vulnerability. Although senescence acts acutely as a tumor suppressor mechanism, chronically it also contributes to inflammation in aged tissue through the senescence-associated secretory phenotype (SASP). Hence, removal of senescent cells in vivo improves healthspan and lifespan, although pharmacological “senolytic” approaches tend to have toxic side effects, likely limiting the utility of senolytics as tools to promote healthy aging. As proof-of-concept for an alternative approach, suppression of SASP in vivo reduces chronic liver inflammation and delays onset of hepatocellular carcinoma. Recently, we have shown that SASP is dependent on expulsion of cytosolic chromatin fragments (CCF) from the nucleus into the cytoplasm of senescent cells. We have recently linked mitochondrial dysfunction to CCF production through a retrograde mitonuclear signaling pathway. This pathway is blocked by histone deacetylase inhibitors through an unknown mechanism. Unexpectedly, we recently discovered the histone deacetylase HDAC7 localizes in the nucleus of senescent cells, is required for CCF formation, and is sensitive to mitochondrial status. We hypothesize that HDAC7 is a novel component of mitochondria-nucleus retrograde signaling in senescent cells. This proposal has two Aims, to: 1) Determine the mitonuclear signaling role of HDAC7, 2) Determine the nuclear role of HDAC7 in CCF formation. Elucidation of the mechanism of this signaling pathway is of interest to all biologists but can also identify therapeutic targets for reduction of SASP. This approach can uncover alternatives to senolytic drugs for treatment of age-associated disease and promote healthy aging.