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.

已知肺随着年龄的增长而发生变化，包括气道上皮的改变。老年人 肺癌的发病率更高，超过70%的肺癌诊断为65岁以上的人。这 提示老化的肺细胞对致癌物的损伤特别敏感。我们对它是如何产生的知之甚少 随着年龄的增长，肺中的细胞变化可能导致癌变。 我们有令人信服的试验数据显示，MUC 5AC在健康老年人的气道中增加， 以及小鼠衰老模型。我们最近还发现，我们可以增加 MUC 5AC通过诱导氧化应激或产生DNA在来自年轻供体的细胞的气道上皮中的表达 损害这些发现表明，不仅MUC 5AC在老化的肺中增加，而且特异性MUC 5AC在老化的肺中增加。 衰老相关的细胞应激驱动衰老中MUC 5AC/muc 5ac的上调。MUC 5AC的上调 在衰老细胞中的蛋白质是衰老和肺癌风险增加之间的联系。特别是， MUC 5AC的表达增加使气道上皮细胞更容易受到DNA损伤， 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，肺老化导致Sirtuin 1（SIRT 1）减少。据了解，SIRT 1可以发挥 在衰老和DNA损伤中的重要作用。SIRT 1还已知使促分裂原活化蛋白脱乙酰化 激酶磷酸酶1（MKP 1）。SIRT 1活性降低导致MKP 1乙酰化增加， 增加MKP 1活性。抑制来自老年供体的肺细胞中的MKP 1使MUC 5AC恢复到低的年轻状态 程度.这表明它在衰老中MUC 5AC的上调中起关键作用。 这些数据使我们假设：衰老导致细胞变化，增加MUC 5AC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 MUC 5AC的上调。2)阐明了衰老过程与 MUC 5AC，并确定如何使衰老细胞恢复活力。3)确定老化的后果和上调 小鼠肺癌模型中的Muc 5ac。