Lipid signaling in cellular senescence and tissue aging

摘要 这项建议的重点是了解和改善治疗的挑战。 特发性肺纤维化，一种破坏性的间质性肺疾病，没有有效的治疗方法。 长期以来，人们一直在研究肺纤维化中脂质信号和代谢的调节失调，指出 神经鞘脂和神经酰胺通路的变化可能会影响病理。近年来， 人们越来越多地注意到肺中衰老细胞作为一个关键因素可能发挥的作用。 导致肺纤维化。衰老细胞表达炎症因子，包括信号脂质， 这可能会推动纤维化过程。目前的问题包括为什么衰老的细胞在 以及如何减轻这些患者的促炎活性。一个推论是 防止衰老细胞的形成，阻断其脂质信号和/或促进其清除 从肺中排出可能会防止肺纤维化或阻止疾病进展。 重要的是，鞘磷脂途径和细胞衰老之间可能存在直接联系。 神经酰胺已经被证明在其他增殖的细胞中诱导衰老。我们的研究已经 被牵连的脂质过氧化及其醛的最终产物，如4-羟基壬烯醛是关键 加速衰老的中介物。转录组、蛋白质组和脂肪组学分析 增殖和衰老的肺细胞将被用来确定关键的衰老因素和网络 这可能指向导致衰老和炎症的特定脂类代谢途径。 发信号。然后我们将检查血脂和调节剂的促进或预防能力 衰老。最后，我们将检查是否可以使用脂类代谢途径的操纵。 促进衰老细胞的清除，从而限制肺纤维化。在这些方面取得成功 随着研究的深入，我们预计将确定有可能进入临床试验的候选治疗药物。

Abstract This proposal is focused on the challenge of understanding and thus improving treatment for idiopathic pulmonary fibrosis, a devastating interstitial lung disease without effective treatments. Deregulation of lipid signaling and metabolism has long been studied in pulmonary fibrosis, pointing to changes in sphingolipid and ceramide pathways that may impact pathology. In recent years, increased attention has been paid to a possible role for senescent cells in the lung as a critical factor driving pulmonary fibrosis. Senescent cells express inflammatory factors, including signaling lipids, which may drive the fibrotic process. Current questions include why senescent cells accumulate in these patients and how their pro-inflammatory activity might be mitigated. An inference is that preventing formation of senescent cells, blocking their lipid signaling and/or promoting their clearance from the lung might prevent pulmonary fibrosis or block disease progression. Importantly, there may be a direct link between sphingolipid pathways and cellular senescence. Ceramides have been shown to induce senescence in otherwise proliferating cells. Our studies have implicated lipid peroxidation and its aldehyde end-products such as 4-hydroxynonenal as key mediators of accelerated senescence. Transcriptomic, proteomic and lipidomic analysis of proliferative and senescent lung cells will be used to identify key senescence factors and networks that may point to the specific lipid metabolic pathways that drive senescence and inflammatory signaling. We will then examine lipids and modulators for the ability to promote or prevent senescence. Finally, we will examine whether manipulation of lipid metabolic pathways can be used to potentiate clearance of senescent cells and thereby limit pulmonary fibrosis. With success in these studies, we anticipate identification of candidate therapeutics with potential to move to clinical trials.