Progenitor cell states contributing to aging and lung cancer

祖细胞状态导致衰老和肺癌

• 批准号: 10362891
• 负责人: MARCIA HAIGIS
• 金额: $ 43.04万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10362891
• 关键词: Adult; Age; Aging; Alveolar; Alveolar Cell; Cancer Etiology; Cell Aging; Cell model; Cells; Cessation of life; Cholesterol; Chromatin; Colorectal Cancer; Data; Disease; Distal; Epigenetic Process; Epithelial Cells; Functional disorder; Gene Expression; Genes; Genetically Engineered Mouse; Growth; Homeostasis; Human; Image; Impairment; Intervention; Lead; Link; Lipids; Lung; Lung Adenocarcinoma; Lung Neoplasms; Lung diseases; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of prostate; Maps; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methyltransferase; Modeling; Modification; Molecular; Mus; Natural regeneration; Organoids; Pathway interactions; Population; Predisposition; Process; Regulation; Reporting; Resolution; Respiratory physiology; Risk Factors; Role; Smoking; Source; Steroids; Structure; Study models; Sum; System; Technology; Testing; age effect; aged; alveolar epithelium; alveolar type II cell; base; cancer initiation; cell age; experience; in vivo Model; injury and repair; insight; lung cancer cell; lung development; lung injury; malignant breast neoplasm; metabolome; metabolomics; molecular modeling; mortality; mouse model; novel; prevent; progenitor; self renewing cell; single cell sequencing; stem cell biology; stem cell function; stem cells; synergism; tumor; tumor initiation; tumor metabolism; tumor progression; tumorigenesis

Progenitor cell states contributing to aging and lung cancer Abstract Lung cancer is the single largest contributor to global cancer mortality. With the exception of smoking, age is the single biggest risk factor for all major lung diseases, including cancer, highlighting the role of age-associated changes in the lung for mortality. Metabolic changes and epigenetic alterations are both hallmarks of aging, but little is known about how aging specifically impacts the lung and in particular lung progenitor cells. Furthermore, the synergy between metabolism and epigenetic states is emerging as an exciting new field for which implications in disease including cancer are only beginning to be explored. Preliminary data we have collected suggest that both metabolic and epigenetic changes accompany aging in lung alveolar type II (AT2) cells, the primary cell-of- origin of the most common form of lung cancer, lung adenocarcinoma. Our study will test the hypothesis that alterations in metabolic pathways driven by epigenetic changes in AT2 cells contribute to increased tumor initiation during aging. Firstly, we will map metabolic and epigenetic changes in aged AT2 cells using state of the art technologies that will enable resolution of these differences onto highly select populations and even single cells. Furthermore, we will create new models to study the effects of aging in cancer. New organoid models of lung cancer initiation will be developed to support rapid modeling of the cellular and molecular aspects of cancer in aged cells. Genetically engineered mouse models will be derived to model tumorigenesis in the aging lung. Finally, we will probe the specific mechanism by which loss of epigenetic modifications, mediated by the methyltransferase G9a, during aging contributes to increased tumor initiation through dysregulation of metabolic genes and the metabolome. These studies will combine the strengths of two experienced PIs with expertise in aging, metabolism, stem cell biology and cancer to generate new models of lung cancer and provide significant insight into the synergy of two major hallmarks of aging in the most-deadly form of cancer.

祖细胞状态与衰老和肺癌有关 摘要 肺癌是全球癌症死亡率的最大贡献者。除吸烟外，年龄是 包括癌症在内的所有主要肺部疾病的单一最大风险因素，突出了与年龄相关的作用 肺部的变化导致死亡。代谢变化和表观遗传变化都是衰老的标志，但 关于衰老如何具体影响肺，特别是肺祖细胞，人们知之甚少。此外， 新陈代谢和表观遗传状态之间的协同作用正在成为一个令人兴奋的新领域，它的含义是 包括癌症在内的疾病方面的研究才刚刚开始。我们收集的初步数据表明， 随着年龄的增长，肺泡II型(AT2)细胞的代谢和表观遗传学变化都会发生。 肺癌的起源最常见的形式是肺腺癌。我们的研究将检验这一假设 AT2细胞表观遗传学变化驱动的代谢途径改变导致肿瘤增加 老化过程中的启动。首先，我们将使用状态映射老化的AT2细胞的代谢和表观遗传变化 ART技术将使这些差异能够解决到高度精选的人群，甚至是单身 细胞。此外，我们将创建新的模型来研究衰老对癌症的影响。新的有机体模型 将开发肺癌启动以支持对癌症的细胞和分子方面的快速建模 在老化的细胞中。基因工程小鼠模型将被用来模拟老化肺中的肿瘤发生。 最后，我们将探讨表观遗传修饰丢失的具体机制，由 甲基转移酶G9a在衰老过程中通过代谢失调促进肿瘤的发生 基因和代谢物。这些研究将结合两名经验丰富的个人投资经理的优势和专业知识 衰老、新陈代谢、干细胞生物学和癌症产生了新的肺癌模型并提供了显著的 洞察衰老的两个主要特征在最致命的癌症中的协同作用。