课题基金 / 基金详情

Dissecting the interplay between aging, genotype and the microenvironment in lung cancer

Dissecting the interplay between aging, genotype and the microenvironment in lung cancer
剖析肺癌中衰老、基因型和微环境之间的相互作用
批准号:
10491833
负责人:
Monte Meier Winslow
金额:
$47.18万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-30 至 2026-06-30

项目摘要

项目成果

Monte Meier Winslow的其他基金

相似基金

相关文献

中文摘要
翻译
项目总结 癌症主要是老年人的一种疾病。虽然这在一定程度上是由于基因组的顺序获取 变化,衰老也与一系列变化有关,这些变化可能影响肿瘤的启动和生长。 这些“衰老的标志”涉及多种途径,影响癌症的发生并导致全身性 改变。然而,尽管衰老与癌症之间有非常密切的联系,或者可能正因为如此, 关于癌细胞内在的、微环境的和全身性的与年龄相关的变化如何影响,我们知之甚少。 癌症的发生和生长。基因工程小鼠模型独特地使定义的 具有明确的时间控制的正常成年细胞的基因改变。人类肺癌已经建立了模型 使用基因工程小鼠模型,这些肿瘤概括了早期人类的许多特征 肺腺癌。为了提高体内肿瘤模型的范围和精度,我们集成了 传统的基因工程小鼠模型,基于CRISPR/Cas9的体细胞基因组工程,以及 采用统计学方法的定量基因组学。CRISPR/Cas9介导的基因偶联肿瘤条码 灭活和高通量条形码测序(TUBA-SEQ)能够定量分析 关于肿瘤起始和原发肿瘤生长的各个方面的大量基因面板。这些型号可以 从而区分衰老和突变事件的影响,同时提供一定程度的精确度,使我们能够 检测不同年龄背景下肿瘤抑制功能的差异。在目标1中,我们将量化相互作用 年龄与肿瘤抑制基因功能之间的关系。我们的体内实验将定义衰老是否会增加 或降低肿瘤启动的绝对效率,并揭示衰老对 不同的肿瘤抑制基因对肿瘤的启动和生长的影响。在目标2中,我们将确定肺部肿瘤是如何 微环境和肺癌细胞本身会随着年龄的增长而变化。我们将阐明肿瘤的影响 基因对不同年龄的微环境的影响,并确定年龄相关的生长变化是否 伴随着癌细胞状态的巨大差异。在目标3中,我们将解开细胞自治 青年小鼠和老年小鼠肿瘤发生的差异及其对肿瘤抑制功能的影响 特别是由于局部组织和全身宿主环境的老化。这些实验将提供洞察力 年龄依赖的基因特异性效应主要是癌细胞固有的,还是由 微环境或整个有机体环境。通过改变癌细胞的年龄和基因,以及 微环境和寄主年龄,我们将对这些因素的贡献有前所未有的了解 涉及肺癌发生的多个方面。最终,这些发现可能会对癌症产生重要的影响。 预防、检测和治疗。
英文摘要
PROJECT SUMMARY Cancer is primarily a disease of the old. While this is due in part to the sequential acquisition of genomic alterations, aging is also associated with a constellation of changes that could impact tumor initiation and growth. These “hallmarks of aging” involve diverse pathways that impinge on carcinogenesis and lead to systemic changes. However, despite the very close association between aging and cancer, or perhaps because of it, very little is known about how cancer cell-intrinsic, microenvironmental, and systemic age-related changes impact cancer initiation and growth. Genetically engineered mouse models uniquely enable the introduction of defined genetic alterations into normal adult cells with defined temporal control. Human lung cancer has been modeled using genetically engineered mouse models, and these tumors recapitulate many features of early-stage human lung adenocarcinoma. To increase the scope and precision of in vivo cancer modeling, we integrated conventional genetically engineered mouse models, CRISPR/Cas9-based somatic genome engineering, and quantitative genomics with statistical approaches. Tumor barcoding coupled with CRISPR/Cas9-mediated gene inactivation and high-throughput barcode sequencing (Tuba-seq) enables quantitative analysis of the effects of large panels of genes on tumor initiation and various facets of autochthonous tumor growth. These models can thus distinguish the effects of aging from mutational events while affording a level of precision that allows us to detect differences in tumor suppressor function across age contexts. In Aim 1, we will quantify the interaction between age and tumor suppressor gene function. Our in vivo experiments will define whether aging increases or decreases the absolute efficiency of tumor initiation and uncover the impact of aging on the importance of diverse tumor suppressor genes on tumor initiation and growth. In Aim 2. we will determine how the lung tumor microenvironment and lung cancer cells themselves change with age. We will elucidate the impact of tumor genotype on the microenvironment across age and determine whether age-dependent changes in growth are accompanied by dramatic differences in cancer cell state. In Aim 3, we will disentangle cell-autonomous differences in tumors developing in young and aged mice from effects on tumor suppressor function driven specifically by aging of the local tissue and systemic host environments. These experiments will provide insight into whether age-dependent genotype-specific effects are largely cancer cell-intrinsic or driven by the shifts in the microenvironment or whole organism environment. By permuting cancer cell age and genotype, as well as microenvironment and host age, we will gain an unprecedented understanding of the contribution of these factors to multiple aspects of lung carcinogenesis. Ultimately, these findings could have important implication for cancer prevention, detection, and treatment.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Dissecting the interplay between aging, genotype and the microenvironment in lung cancer
  • 批准号:
    10362239
  • 项目类别:
  • 资助金额:
    $48.01万
  • 财政年份:
    2021
  • 负责人:
    Monte Meier Winslow
  • 依托单位:
Genetic dissection of oncogenic Kras signaling
  • 批准号:
    10441550
  • 项目类别:
  • 资助金额:
    $43.79万
  • 财政年份:
    2021
  • 负责人:
    Monte Meier Winslow
  • 依托单位:
Genetic dissection of oncogenic Kras signaling
  • 批准号:
    10656203
  • 项目类别:
  • 资助金额:
    $42.82万
  • 财政年份:
    2021
  • 负责人:
    Monte Meier Winslow
  • 依托单位:
Genetic dissection of oncogenic Kras signaling
  • 批准号:
    10296608
  • 项目类别:
  • 资助金额:
    $46.82万
  • 财政年份:
    2021
  • 负责人:
    Monte Meier Winslow
  • 依托单位:
国内基金
海外基金
补阳还五汤通过AGE-RAGE通路调控脓毒症免疫失衡的机制与转化研究
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
  • 批准号:
    JCZRQN202500010
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2025
  • 负责人:
  • 依托单位:
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
  • 批准号:
    2025JJ70209
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2025
  • 负责人:
    雷芬芳
  • 依托单位:
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
  • 批准号:
    --
  • 项目类别:
    面上项目
  • 资助金额:
    --
  • 批准年份:
    2024
  • 负责人:
    万荣
  • 依托单位: