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

肺部老化增加气道上皮中的MUC5AC，增加致癌风险

• 批准号: 10583805
• 负责人: Kristina L Bailey
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583805
• 关键词: Accounting; Acetylation; Address; Age; Aging; Cancer Etiology; Cancer Patient; Cells; Cellular Stress; Cessation of life; Chronic Obstructive Pulmonary Disease; DNA Damage; Data; Deacetylation; Development; Elderly; Enrollment; Environment; Epithelial Cells; Individual; K-ras mouse model; Knockout Mice; Link; Lung; Lung diseases; MAPK1 gene; Malignant Neoplasms; Malignant neoplasm of lung; Mitogen-Activated Protein Kinases; Modeling; Mucins; Mus; Oxidative Stress; Oxidative Stress Induction; Patients; Play; Predisposition; Process; Production; Rejuvenation; Research Personnel; Resveratrol; Risk; Risk Factors; Role; SIRT1 gene; System; United States; Up-Regulation; Urethane; Veterans; aged; airway epithelium; cancer diagnosis; carcinogenesis; carcinogenicity; cell age; cigarette smoking; human old age (65+); idiopathic pulmonary fibrosis; lung carcinogenesis; lung development; mouse model; multidisciplinary; phosphatase-1 kinase; tumor; tumorigenesis

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.

已知肺随着衰老而发生变化，包括气道上皮的改变。老年人 肺癌发生率较高，在65岁以上的患者中诊断出70％以上的肺癌。 表明老化的肺部细胞对致癌性损伤特别敏感。关于如何 随着肺部衰老的细胞变化可能导致致癌。 我们有令人信服的试点数据，显示健康老年人的气道中MUC5AC有所增加，因为 以及在老化的鼠模型中。我们最近还发现，我们可以增加 通过诱导氧化应激或产生DNA 损害。这些发现表明，不仅MUC5AC在衰老的肺中增加，而且是特定的 与衰老相关的细胞应力驱动MUC5AC/MUC5AC在衰老中的上调。 MUC5AC的上调 在较老的细胞中，是衰老与肺癌患风险增加之间的联系。尤其， MUC5AC的表达增加使气道上皮更容易受到DNA损伤，然后 有可能创造有利于癌变的环境。 我们的初步数据表明，肺老化会导致SIRTUIN 1（SIRT1）的降低。 Sirt 1众所周知 在衰老和DNA损伤中的重要作用。 SIRT1也已知脱乙酰酸丝分裂原激活蛋白 激酶磷酸酶1（MKP1）。 SIRT1活性降低会导致MKP1的乙酰化增加，这 增加MKP1活性。抑制来自老年供体的肺细胞中MKP1的抑制作用可将MUC5AC恢复到低年轻，年轻 水平。这表明它在MUC5AC在衰老中的上调中起关键作用。 这些数据导致我们假设：衰老会导致细胞变化，从而增加MUC5AC表达， 促进肺癌发展。在此提案中，我们将1）确定促进的衰老机制 MUC5AC的上调。 2）阐明将老化过程与增加表达联系起来的机制 MUC5AC，并确定如何恢复衰老的细胞。 3）确定衰老的后果 MUC5AC在肺癌的鼠模型中。