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.

众所周知，肺部会随着衰老而发生变化，包括气道上皮的变化。老年人 肺癌发病率较高，超过 70% 的肺癌是在 65 岁以上人群中诊断出来的。 表明老化的肺细胞对致癌损伤特别敏感。对于如何进行知之甚少 肺部细胞随着衰老而发生的变化可能导致癌变。 我们有令人信服的试验数据显示，MUC5AC 在健康老年人的气道中增加，因为 以及小鼠衰老模型中的情况。我们最近还发现我们可以增加 年轻供体细胞气道上皮中的 MUC5AC 通过诱导氧化应激或产生 DNA 损害。这些发现表明，MUC5AC 不仅在衰老的肺部中增加，而且特定的 衰老相关的细胞应激会导致衰老过程中 MUC5AC/muc5ac 的上调。 MUC5AC的上调 在老年细胞中，衰老与罹患肺癌的风险增加之间存在联系。尤其， MUC5AC 表达增加使气道上皮更容易受到 DNA 损伤，然后 可能会创造一个有利于致癌的环境。 我们的初步数据表明，肺衰老会导致 Sirtuin 1 (SIRT1) 的减少。 SIRT 1 已知可发挥 在衰老和 DNA 损伤中发挥着重要作用。 SIRT1 还可以使丝裂原激活蛋白脱乙酰化 激酶磷酸酶 1 (MKP1)。 SIRT1 活性降低会导致 MKP1 乙酰化增加，从而 增加 MKP1 活性。抑制老年供体肺细胞中的 MKP1 可将 MUC5AC 恢复到低水平、年轻状态 水平。这表明它在衰老过程中 MUC5AC 的上调中发挥着关键作用。 这些数据使我们做出假设： 衰老会导致细胞变化，从而增加 MUC5AC 表达， 促进肺癌的发展。在本提案中，我们将 1）确定促进衰老的机制 MUC5AC 的上调。 2) 阐明衰老过程与表达增加之间的联系机制 MUC5AC，并确定如何使衰老细胞恢复活力。 3) 识别衰老和上调的后果 小鼠肺癌模型中的 Muc5ac。