Epigenetic mechanisms of therapeutic resistance

治疗耐药的表观遗传机制

基本信息

  • 批准号:
    10261466
  • 负责人:
  • 金额:
    $ 36.61万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-11 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Cellular phenotypic heterogeneity is a key mechanism underlying neoplastic disease progression and therapeutic resistance, yet its regulation is poorly understood at the molecular level. We have found that elevated therapeutic resistance is associated with higher levels of cell-to-cell transcriptomic heterogeneity and that decreasing such heterogeneity by modulating the activity of epigenetic histone-modifying enzymes such as KDM5B improves responses to treatment. We also determined that acquired resistance to epigenetic drug agents, including KDM5 and BET bromodomain inhibitors, is due to epigenetic mechanisms, whereas acquired endocrine resistance reflects a selection for a pre-existing, genetically distinct sub-populations of cells. The goal of this Project is to investigate the population dynamics of cellular phenotypic heterogeneity in response to and resistance to cancer therapies in luminal estrogen receptor positive (ER+) and triple-negative breast cancer (TNBC). Our hypothesis is that cellular states governed by epigenetic regulators are highly variable and dynamic and that this underlies acquired therapeutic resistance. We also hypothesize that by modulating the activity of epigenetic regulators and by identifying mechanisms of synthetic lethality and the acquired resistance to epigenetic agents, we can decrease transcriptomic heterogeneity and improve therapeutic response. To test our hypotheses, we will characterize the impact of genetic and epigenetic heterogeneity on acquired resistance to endocrine, chemo-, and epigenetic therapies (Aim 1). We will use barcoded cells to follow population dynamics during the development of acquired resistance, characterize the epigenetic landscape and transcriptomic heterogeneity of drug-tolerant and -resistant populations, and build mathematical models based on experimental data to predict the evolution of therapeutic resistance to different agents. Additionally, to define synthetic-lethal interactions and mechanism of acquired resistance to epigenetic therapies we will perform CRISPR/Cas9 screens (Aim 2) in ER+ and TNBC cell lines that are sensitive versus resistant to epigenetic agents. Overall, the project will significantly advance our knowledge of the regulation of phenotypic heterogeneity and the role this plays in therapeutic responses and resistance.
项目总结/摘要 细胞表型异质性是肿瘤疾病进展的关键机制, 治疗耐药性,但其调节在分子水平上知之甚少。我们发现, 治疗抗性与细胞间转录组异质性水平较高有关, 通过调节表观遗传组蛋白修饰酶的活性来降低这种异质性, KDM 5 B改善了对治疗的反应。我们还确定了对表观遗传药物的获得性耐药性 药物,包括KDM 5和BET布罗莫结构域抑制剂,是由于表观遗传机制,而获得性 内分泌抗性反映了对预先存在的、遗传上不同的细胞亚群的选择。目标 本项目的目的是研究细胞表型异质性的群体动力学, 腔雌激素受体阳性(ER+)和三阴性乳腺癌对癌症治疗的耐药性 (TNBC)。我们的假设是,由表观遗传调节器控制的细胞状态是高度可变和动态的 这是获得性治疗耐药性的基础。我们还假设,通过调节 表观遗传调节因子,并通过确定合成致死性和获得性抗性的机制, 表观遗传剂,我们可以减少转录组异质性和改善治疗反应。来测试我们 假设,我们将描述遗传和表观遗传异质性对获得性耐药性的影响, 内分泌、化疗和表观遗传疗法(目标1)。我们将使用条形码细胞来跟踪种群动态 在获得性抗性的发展过程中,表征表观遗传景观和转录组学 耐药和耐药群体异质性,并建立数学模型的基础上,实验 数据来预测对不同药剂的治疗抗性的演变。另外,为了定义合成致死 我们将利用CRISPR/Cas9技术研究对表观遗传疗法的获得性抗性的相互作用和机制, 在ER+和TNBC细胞系中筛选(目标2)对表观遗传试剂敏感与抗性的细胞系。总体看 该项目将大大提高我们对表型异质性调节的认识,以及这种调节在表型异质性中的作用。 在治疗反应和抵抗中起作用。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

KORNELIA POLYAK其他文献

KORNELIA POLYAK的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('KORNELIA POLYAK', 18)}}的其他基金

Administrative Core - New therapeutic vulnerabilities in breast cancer
行政核心 - 乳腺癌的新治疗漏洞
  • 批准号:
    10261469
  • 财政年份:
    2020
  • 资助金额:
    $ 36.61万
  • 项目类别:
Epigenetic mechanisms of therapeutic resistance
治疗耐药的表观遗传机制
  • 批准号:
    10627962
  • 财政年份:
    2020
  • 资助金额:
    $ 36.61万
  • 项目类别:
Administrative Core - New therapeutic vulnerabilities in breast cancer
行政核心 - 乳腺癌的新治疗漏洞
  • 批准号:
    10627981
  • 财政年份:
    2020
  • 资助金额:
    $ 36.61万
  • 项目类别:
Epigenetic mechanisms of therapeutic resistance
治疗耐药的表观遗传机制
  • 批准号:
    10434103
  • 财政年份:
    2020
  • 资助金额:
    $ 36.61万
  • 项目类别:
New therapeutic vulnerabilities in breast cancer
乳腺癌新的治疗弱点
  • 批准号:
    10434102
  • 财政年份:
    2020
  • 资助金额:
    $ 36.61万
  • 项目类别:
Epigenetic mechanisms of therapeutic resistance
治疗耐药的表观遗传机制
  • 批准号:
    10023397
  • 财政年份:
    2020
  • 资助金额:
    $ 36.61万
  • 项目类别:
Administrative Core - New therapeutic vulnerabilities in breast cancer
行政核心 - 乳腺癌的新治疗漏洞
  • 批准号:
    10023400
  • 财政年份:
    2020
  • 资助金额:
    $ 36.61万
  • 项目类别:
New therapeutic vulnerabilities in breast cancer
乳腺癌新的治疗弱点
  • 批准号:
    10627961
  • 财政年份:
    2020
  • 资助金额:
    $ 36.61万
  • 项目类别:
New therapeutic vulnerabilities in breast cancer
乳腺癌新的治疗弱点
  • 批准号:
    10261465
  • 财政年份:
    2020
  • 资助金额:
    $ 36.61万
  • 项目类别:
New therapeutic vulnerabilities in breast cancer
乳腺癌新的治疗弱点
  • 批准号:
    10023396
  • 财政年份:
    2020
  • 资助金额:
    $ 36.61万
  • 项目类别:

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 36.61万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 36.61万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 36.61万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 36.61万
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 36.61万
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 36.61万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 36.61万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 36.61万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 36.61万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 36.61万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了