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.

祖细胞状态导致衰老和肺癌 抽象的 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最大危险因素，突出了与年龄相关的作用 死亡率的肺部变化。代谢变化和表观遗传改变都是衰老的标志，但 关于衰老如何特异性影响肺，尤其是肺祖细胞细胞，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 在包括癌症在内的疾病中，才刚刚开始探索。我们收集的初步数据表明 代谢和表观遗传学变化伴随着肺肺泡II型（AT2）细胞的衰老，这是主要细胞 肺癌最常见形式的起源，肺腺癌。我们的研究将检验以下假设 由AT2细胞表观遗传变化驱动的代谢途径的改变，导致肿瘤增加 衰老期间的启动。首先，我们将使用状态 可以将这些差异解决到高度选择人群甚至单一的艺术技术 细胞。此外，我们将创建新的模型来研究癌症衰老的影响。新的器官模型 将开发肺癌的开始来支持癌症细胞和分子方面的快速建模 在老年细胞中。基因工程的小鼠模型将得出模型，以模拟衰老肺中的肿瘤发生。 最后，我们将探究特定机制，通过该机制，表观遗传修饰的丧失，由 甲基转移酶G9A，在衰老期间，通过代谢失调有助于增加肿瘤的启动 基因和代谢组。这些研究将结合两个经验丰富的PI的优势和专业知识 衰老，代谢，干细胞生物学和癌症，以产生新的肺癌模型并提供重要的 深入了解最令人垂涎​​的癌症的两个主要衰老标志的协同作用。