Pulmonary aging increases MUC5AC in the airway epithelium, increasing the risk of carcinogenesis

众所周知，随着年龄的增长，肺会发生变化，包括呼吸道上皮的变化。老年人 有更高的肺癌发病率，超过70%的肺癌是在65岁以上的人中诊断出来的。这 这表明衰老的肺细胞对致癌的侮辱特别敏感。人们对此知之甚少 随着肺部年龄的增长，细胞的变化可能导致癌症的发生。 我们有令人信服的飞行员数据显示，健康老年人的呼吸道中MUC5AC增加，因为 在衰老的小鼠模型中也是如此。我们最近还发现，我们可以增加 年轻供者呼吸道上皮细胞中MUC5AC通过诱导氧化应激或产生DNA 损坏。这些发现表明，不仅MUC5AC在衰老的肺中增加，而且特异性的 衰老相关的细胞应激促使MUC5AC/MUC5AC在衰老过程中上调。MUC5AC的上调 在衰老和患肺癌风险增加之间起着联系的作用。特别是， MUC5AC的表达增加使呼吸道上皮更容易受到DNA损伤，从而 潜在地创造了一个有利于致癌的环境。 我们的初步数据表明，肺老化会导致Sirtuin 1(SIRT1)的减少。众所周知，Sirt 1扮演着一种 在衰老和DNA损伤方面的突出作用。已知的SIRT1还可以使丝裂原激活蛋白去乙酰化 蛋白激酶磷酸酶1(MKP1)。SIRT1活性降低导致mkp1乙酰化增加，从而 增加mkp1活性。抑制老年供者肺细胞中的mkp1使MUC5AC恢复到低、年轻的状态 级别。这表明它在MUC5AC在衰老过程中的上调中起着关键作用。 这些数据让我们假设：衰老导致细胞变化，增加MUC5AC的表达， 促进肺癌的发展。在这项提案中，我们将1)确定促进 MUC5AC的表达上调。2)阐明衰老过程与基因表达增加之间的联系机制 MUC5AC，并确定如何使衰老的细胞恢复活力。3)确定老龄化和上调的后果 小鼠肺癌模型中的MUC5AC。

The lung is known to undergo changes with aging, including alterations in the airway epithelium. Older people have higher rates of lung cancer, with over 70% of lung cancers diagnosed in those over age 65. This suggests that the aged lung cell is particularly sensitive to carcinogenic insults. Very little is known about how cellular changes with aging in the lung may lead to carcinogenesis. We have compelling pilot data showing that MUC5AC is increased in the airways of healthy older people, as well as in a murine model of aging. We have also recently found that we can increase the expression of MUC5AC in the airway epithelium of cells from young donors by inducing oxidative stress or producing DNA damage. These findings suggest that not only is MUC5AC increased in the aging lung, but also that specific aging-related cell stresses drive the upregulation of MUC5AC/muc5ac in aging. The upregulation of MUC5AC in older cells serves as a link between aging and the increasing risk of developing lung cancer. In particular, the increased expression of MUC5AC makes the airway epithelium more susceptible to DNA damage and then potentially creates an environment that is favorable to carcinogenesis. Our preliminary data suggest that lung aging leads to decreases in Sirtuin 1 (SIRT1). SIRT 1 is known to play a prominent role in aging and DNA damage. SIRT1 is also known to deacetylate Mitogen-activated protein kinase phosphatase 1 (MKP1). Decreased SIRT1 activity leads to increased acetylation of MKP1, which increases MKP1 activity. Inhibition of MKP1 in lung cells from aged donors restores MUC5AC to low, youthful levels. This suggests it plays a key role in the upregulation of MUC5AC in aging. These data led us to hypothesize that: Aging leads to cellular changes that increase MUC5AC expression, promoting lung cancer development. In this proposal we will 1) Determine the aging mechanisms that promote the upregulation of MUC5AC. 2) Elucidate the mechanisms linking aging processes to increased expression of MUC5AC, and determine how to rejuvenate aged cells. 3) Identify the consequences of aging and upregulated Muc5ac in a murine model of lung cancer.