Profiling the Fluid Assisted Dissemination of Pre-malignant cells in Fallopian Tubes

分析输卵管癌前细胞的液体辅助传播

基本信息

  • 批准号:
    10718158
  • 负责人:
  • 金额:
    $ 61.89万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-07 至 2028-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY The high mortality rate in ovarian cancers is explained in part, by late-stage clinical diagnosis where intraperitoneal tumor burden is already prevalent and widespread. Shedding and implantation of transformed secretory cells, originating from the fallopian tube, is considered one of the main initiators of ovarian cancer. During the early stages of this disease, secretory fallopian tube cells gain mutations that support migration (against the direction of fluid flow) to the ends of the fallopian tubes (fimbriae). At the fimbriae, the mutated fallopian tube cells form small early precursor lesions. Both the ovaries and fallopian tubes are suspended within the abdominal cavity, where the environment further exposes early precursor tumor cells to dynamic shear stresses. We therefore hypothesize that the fluidic shear stress stimulates the early precursor lesions in the fallopian tubes and modulates their dissemination to the ovary and peritoneal organs. In order to test this hypothesis, we will utilize microfluidic devices and bioreactors to circulate cell growth medium around transformed human and mouse fallopian tube cell lines that are supported on an agarose-collagen, polysaccharide-protein scaffold. Human immortalized fallopian tube cells with varying degrees of genetic mutation will be probed for changes in cell replication, migration, invasion, cell death, and genetic variation after stimulation of shear stress. Our preliminary data suggests a robust increase in the expression of GPRC5A in fallopian tube secretory epithelial cells (FTSEC) under shear stress stimulation. Therefore, we will validate this discovery in FTSEC cell lines with driver mutations and patient-derived cells, and investigate the GPRC5A molecular pathway and its components that are activated in FTSEC under shear stress stimulation, by utilizing gain-of-function and loss-of-function assays. Shear stressed and static control mutated fallopian tube cells will be tested for stemness and the capacity to initiate tumors in immunodeficient mice. Stimulated transformed fallopian tube cells will also be injected into immunocompromised mice to investigate the cell’s ability to colonize and form tumors. These studies will also be performed in mice with intact immune systems in order to assess whether immune cells impact growth and dissemination. Given that no published studies have yet identified the role of shear stresses in dissemination of early precursor lesions in ovarian cancers, the proposed work can potentially have much broader impact. For example, with our dynamic microfluidic and 3D bioreactor models, mechanotransduction and immunotherapy drugs can be screened for development of effective cancer therapies. The components of the shear stress-induced mechanotransduction that are identified in our proposed work, could also be utilized in early detection of ovarian cancers. As a result, the important role of shear stresses in the fluidic niches of ovarian cancers will be established. Lastly, our study on the mechanical regulation of transformed epithelial cells will be highly relevant to fundamental biology and clinical translational alike.
项目摘要 卵巢癌的高死亡率部分通过后期临床诊断来解释 腹膜内肿瘤伯恩已经普遍存在且宽度。转换和植入转化 源自输卵管的秘书细胞被认为是卵巢癌的主要启动者之一。 在这种疾病的早期阶段,秘书输卵管细胞获得了支持迁移的突变 (靠在流体流动的方向上)到输卵管(fimbriae)的末端。在fimbriae,突变 输卵管细胞形成小早期前体病变。卵巢和输卵管都被悬挂在 腹腔,环境进一步将早期前体肿瘤细胞暴露于动态剪切 压力。因此,我们假设流体剪切应力刺激了早期的前体病变 输卵管并调节其传播到卵巢和腹膜器官。 为了检验该假设,我们将利用微流体设备和生物反应器来循环细胞生长培养基 围绕在琼脂糖 - 胶原上支撑的转化的人和小鼠输卵管细胞系, 多糖蛋白脚手架。人生永生的输卵管细胞,具有不同程度的普通元 将探测突变的细胞复制,迁移,侵袭,细胞死亡和遗传变异的变化 刺激剪切应力。我们的初步数据表明,GPRC5a在 在剪切应力刺激下,输卵管分泌上皮细胞(FTSEC)。因此,我们将验证这个 在具有驱动器突变和患者衍生细胞的FTSEC细胞系中发现,并研究GPRC5A 通过使用,在剪切应力刺激下在FTSEC中激活的分子途径及其成分,通过使用 功能障碍和功能丧失测定法。剪切应力和静态对照突变的输卵管细胞将 在免疫缺陷小鼠中启动肿瘤的肿瘤的能力进行测试。刺激转换 输卵管细胞也将被注入免疫功能低下的小鼠,以研究细胞定居的能力 并形成肿瘤。这些研究也将在具有完整免疫系统的小鼠中进行,以评估 免疫细胞是否影响生长和传播。鉴于尚无公开研究确定 剪切应力在卵巢癌中早期前体病变传播中的作用,拟议的工作可以 可能产生更大的影响。例如,使用我们的动态微流体和3D生物反应器模型, 可以筛选机械转导和免疫疗法药物以开发有效的癌症疗法。 剪切应力诱导的机械转导的成分是在我们提出的工作中确定的 也可以在早期检测卵巢癌中使用。结果,剪切应力在 将建立卵巢癌的液体壁ni。最后,我们对机械调节的研究 转化的上皮细胞将与基本生物学和临床翻译高度相关。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据

数据更新时间:2024-06-01

相似国自然基金

腹腔巨噬细胞通过IL-16信号通路介导子宫内膜异位症慢性腹部疼痛
  • 批准号:
    32371043
  • 批准年份:
    2023
  • 资助金额:
    50 万元
  • 项目类别:
    面上项目
去泛素化酶PSMD8与YWHAE相互作用在卵巢癌腹腔种植转移中的分子机制研究
  • 批准号:
    82303503
  • 批准年份:
    2023
  • 资助金额:
    30 万元
  • 项目类别:
    青年科学基金项目
巨噬细胞GEF-H1介导的铁死亡加重腹腔感染肠屏障损伤的机制研究
  • 批准号:
    82300651
  • 批准年份:
    2023
  • 资助金额:
    30 万元
  • 项目类别:
    青年科学基金项目
牙鲆腹腔源MHCII和CD80/86阳性外泌体对抗原特异性免疫应答调控机制的研究
  • 批准号:
    32373160
  • 批准年份:
    2023
  • 资助金额:
    50 万元
  • 项目类别:
    面上项目
Serotonin信号轴在精神压力促卵巢癌腹腔扩散中的作用机制及靶向干预
  • 批准号:
    82373033
  • 批准年份:
    2023
  • 资助金额:
    49 万元
  • 项目类别:
    面上项目

相似海外基金

Establishment of the disease concept of laryngeal sarcopenia based on the estimation of the laryngeal muscular force using kinematics
基于运动学估计喉肌力建立喉肌少症疾病概念
  • 批准号:
    21K09630
    21K09630
  • 财政年份:
    2021
  • 资助金额:
    $ 61.89万
    $ 61.89万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
    Grant-in-Aid for Scientific Research (C)
大声発声の喉頭抵抗・呼気努力への依存優位性評価のための新空気力学的検査法の開発
开发一种新的空气动力学测试方法,用于评估大声发声对喉部阻力和呼气力度的依赖性
  • 批准号:
    21K16857
    21K16857
  • 财政年份:
    2021
  • 资助金额:
    $ 61.89万
    $ 61.89万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
    Grant-in-Aid for Early-Career Scientists
Establishment of a method evaluating inappropriateness of loud voice phonation in the development of vocal nodules
声带小结发育过程中大声发声不当评价方法的建立
  • 批准号:
    17K11382
    17K11382
  • 财政年份:
    2017
  • 资助金额:
    $ 61.89万
    $ 61.89万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
    Grant-in-Aid for Scientific Research (C)
The characteristics of chair sit-to-stand movements and its application to the training exercises
椅子坐站动作的特点及其在训练中的应用
  • 批准号:
    16K01605
    16K01605
  • 财政年份:
    2016
  • 资助金额:
    $ 61.89万
    $ 61.89万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
    Grant-in-Aid for Scientific Research (C)
Development of kidney laparoscopic surgery navigator with GPU acceleration by cooperation of physician and sensor
医师与传感器协同开发GPU加速肾脏腹腔镜手术导航仪
  • 批准号:
    15K00291
    15K00291
  • 财政年份:
    2015
  • 资助金额:
    $ 61.89万
    $ 61.89万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
    Grant-in-Aid for Scientific Research (C)