Progenitor cell states contributing to aging and lung cancer

导致衰老和肺癌的祖细胞状态 摘要 肺癌是全球癌症死亡率的最大贡献者。除了吸烟，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，突出了年龄相关的作用 肺部变化与死亡率的关系代谢变化和表观遗传改变都是衰老的标志， 关于衰老如何具体影响肺，特别是肺祖细胞，知之甚少。此外，委员会认为， 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的应用才刚刚开始。我们收集的初步数据表明， 代谢和表观遗传变化都伴随着肺泡II型（AT 2）细胞的衰老， 肺癌的起源最常见的形式，肺腺癌。我们的研究将检验这样一个假设， 由AT2细胞中的表观遗传变化驱动的代谢途径的改变有助于增加肿瘤 在老化过程中启动。首先，我们将使用代谢和表观遗传学的状态来绘制老年AT2细胞的代谢和表观遗传学变化。 艺术技术，将能够解决这些差异高度选择的人口，甚至单一的 细胞此外，我们将创建新的模型来研究衰老对癌症的影响。新的类器官模型 肺癌启动将被开发，以支持癌症的细胞和分子方面的快速建模 老化的细胞。基因工程小鼠模型将被用来模拟衰老肺中的肿瘤发生。 最后，我们将探讨表观遗传修饰丢失的具体机制， 甲基转移酶G9a，在老化过程中有助于增加肿瘤的启动通过失调的代谢 基因和代谢组。这些研究将结合联合收割机的两个经验丰富的PI的优势， 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 深入了解衰老的两个主要标志在最致命的癌症形式中的协同作用。

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.