Role of HDAC7 in senescence-associated inflammation

项目总结 细胞衰老是衰老过程的一个标志，也是慢性病脆弱性的原因之一。 尽管衰老在很大程度上是一种肿瘤抑制机制，但从长期来看，它也有助于 衰老相关分泌表型(SASP)在老年组织中的炎症。因此，删除 体内衰老细胞的数量增加了健康和寿命，尽管药理上的“衰老”方法 往往有毒副作用，可能会限制感觉剂作为促进健康衰老的工具的效用。AS 另一种方法的概念验证：体内抑制SASP可减少慢性肝脏炎症 并延缓肝细胞癌的发病。最近，我们已经表明，SASP依赖于驱逐 胞质染色质碎片(CCF)从细胞核进入衰老细胞的细胞质。我们有 最近通过逆行有丝分裂信号将线粒体功能障碍与CCF的产生联系起来 路径。组蛋白脱乙酰酶抑制剂通过一种未知的机制阻断这一途径。 出乎意料的是，我们最近发现组蛋白脱乙酰酶HDAC7定位于衰老的细胞核 细胞，是形成CCF所必需的，并且对线粒体状态很敏感。我们假设HDAC7是一个 衰老细胞中线粒体-细胞核逆行信号的新成分。这项提案有两个 目的：1)确定HDAC7的有丝分裂核信号作用；2)确定HDAC7的核作用 CCF地层中的HDAC7。阐明这一信号通路的机制是所有人都感兴趣的 但生物学家也可以确定减少SASP的治疗靶点。这种方法可以揭示 用于治疗年龄相关疾病和促进健康衰老的抗衰老药物的替代品。

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.