Effect of Cyclical Intermittent Hypoxia on Lung Cancer Progression

目的：了解老年退伍军人患肺癌风险增加的原因。我们的首要目标是 确定T调节细胞(Tregs)和髓系衍生抑制细胞(MDSC)这两种主要免疫细胞是如何 已知随着年龄的增长会在肺部蓄积，促进肺癌的进展。我们的假设是(目标1)古老 与幼年鼠相比，小鼠的肺中会有更多的Treg和MDSCs，这在 肺癌的背景；(目标2)癌症老年小鼠Tregs和MDSCs的增加将竞争更多 导致癌周围正常肺组织mTOR功能降低的营养物质；(目标3) 老年小鼠体内Tregs的增加将消耗更多的营养物质(精氨酸)，并进一步促进肺癌的发生 进步。研究设计：我们将在亲代Merit中使用相同的小鼠肺癌模型， 三重转基因KrasG12D+；p53fl/fl；肉豆蔻酰化p110fl/fl Rosa-GFP(TT-KPP)小鼠注射cre病毒 (Kras POS小鼠)和注射克隆细胞(Kras NEG小鼠)。这笔赠款的理念创新在于， 我们将首次探索老年小鼠的癌变肺和正常小鼠肺之间的相互作用， 特别是代谢途径，mTOR和营养竞争，精氨酸，因为它们都促进了 在免疫抑制和癌症进展中的作用。方法学：目的1：鉴定免疫细胞表型 在患有肺癌的老年小鼠和年轻小鼠的肺中。初步结果将是定量M-MDSC//特雷格斯 在左肺早期(2 Mm)和晚期(&gt；4 mm)时间点。目的2：评估mTOR通路的作用 对老年和年轻肺癌小鼠的免疫和衰老细胞群的影响。主要结果将是 老年与青年肺癌周围正常肺与癌内4EBP定量比较 老鼠。目的3：探讨老年和幼年小鼠骨髓间充质干细胞、ARG1和精氨酸水平之间的关系 患有肺癌。主要结果是左肺早期(2 Mm)和晚期(&gt；4 mm)的定量M-MDSC。 时间点。探索性：确定吸入宿主导向疗法(HDT)的可行性 旨在使用4D扫描仪破坏螺旋。调查结果：首次提交。临床关系：我们可能 提供老年患者免疫衰老如何促进肺癌进展的证据。 影响/意义：通过了解肺癌中衰老引发的免疫代谢调节， 我们可能会开发一种治疗肺癌的新方法：向正常的、非癌症的人提供更多的营养 阿龙。

Objective: To understand why older Veterans are at increased risk of lung cancer. Our overarching goal is to determine how T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSC), two major immune cells known to accumulate in lungs as we age, promotes lung cancer progression. Our hypothesis is that (Aim 1) old mice will have more Tregs and MDSCs in the lung compared to young mice, and this is more pronounced in the setting of lung cancer; (Aim 2) the increase in Tregs and MDSCs in old mice with cancer will compete for more nutrients that lead to decreased mTOR function in the surrounding normal lung around the cancer; (Aim 3) that the increased Tregs in old mice will consume more nutrients (arginine) and further promote lung cancer progression. Research Design: We will use the same mouse models of lung cancer in the Parent Merit, where Triple Transgenic KrasG12D+; p53fl/fl; myristoylated p110fl/fl ROSA-gfp (TT-Kpp) mice are injected with cre viruses (Kras POS mice) and injected with clone cells (Kras NEG mice). The conceptual innovation of this grant is that we will be the first to explore the interaction between cancerous lung and normal lung in old vs young mice, specifically the metabolic pathway, mTOR and nutrient competition, arginine, as they both promote an increase in immunosuppression and the progression of cancer. Methodology: Aim 1: To identify immune cell phenotype in the lungs of old versus young mice with lung cancer. Primary outcome will be quantitative M-MDSC/TAM/Tregs in the left lung at early (2 mm) and late (>4 mm) time points. Aim 2: To evaluate the role of the mTOR pathway on immune and senescent cell populations in old versus young mice with lung cancer. Primary outcome will be quantitative 4EBP in normal lung surrounding the lung cancer compared to that within the cancer in old vs young mice. Aim 3: To explore the relationship between MDSCs, ARG1, and arginine levels in old versus young mice with lung cancer. Primary outcome will be quantitative M-MDSC in the left lung at early (2 mm) and late (>4 mm) time points. Exploratory: To determine the feasibility of administering inhaled host-directed therapies (HDT) intended on disrupting SPIRAL using 4D scanner. Findings: First submission. Clinical Relationships: We may provide evidence how immunosenescence in older patients contribute to lung cancer progression. Impact/Significance: By understanding Senescence-Provoked Immunometabolic Regulation in Lung Cancer, we may develop a novel treatment approach to lung cancer: deliver more nutrients to normal, non-cancerous lung.