Solving the elusive mechanism of rapamycin action in lymphocytes

解决雷帕霉素在淋巴细胞中作用的难以捉摸的机制

基本信息

  • 批准号:
    8285697
  • 负责人:
  • 金额:
    $ 19.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-08-20 至 2014-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): mTOR is a serine/threonine kinase that is expressed ubiquitously. The mTOR enzyme is present in two cellular complexes, TORC1 and TORC2. mTOR was discovered and named based on its interaction with the drug rapamycin. This compound is an allosteric inhibitor that partially blocks TORC1 activity and generally does not inhibit TORC2 function. Rapamycin treatment of T and B lymphocytes profoundly blocks proliferation triggered by antigen and other mitogens, and rapamycin (sirolimus; Rapamune(R)) is an FDA-approved immunosuppressant. However, rapamycin and analogs have lesser effects on proliferation in other cellular systems including cancer cells. Although the effects of rapamycin on lymphocytes have been studied for 20 years, it remains unclear why the compound induces a profound block of proliferation selectively in lymphocytes. Paradoxically, a novel class of ATP-competitive mTOR kinase inhibitors (TOR-KIs) causes less immunosuppression than rapamycin despite causing more complete inhibition of both TORC1 and TORC2. The goal of this project is to define mechanisms by which rapamycin selectively blocks proliferation of normal lymphocytes. Based on preliminary data, we propose two hypotheses that form the basis of separate specific aims. Aim 1 will test the hypothesis that rapamycin causes more complete and sustained inhibition of S6 kinases, key substrates of TORC1. There are two S6 kinases, S6K1 and S6K2, but their roles in lymphocyte activation and proliferation have not been reported. We will use a novel mouse model that will allow a chemical genetic approach to specifically inhibit S6K activity in normal T and B cells. We will use this model to compare the effects of S6K inhibition with the effects of rapamycin and TOR-KIs. Aim 2 will test the hypothesis that rapamycin inhibits kinase-independent functions of mTOR. We will generate a novel mouse strain in which kinase-dead mTOR can be expressed in a cell-specific manner. This will allow us to test the prediction that lymphocytes expressing kinase-dead mTOR will retain residual proliferation that remains sensitive to rapamycin. We will also begin a candidate approach to test possible kinase-independent mTOR functions. PUBLIC HEALTH RELEVANCE: A drug called rapamycin is used to suppress the immune system and prevent rejection of organ transplants. However, it is not known why rapamycin selectively blocks the activation of immune cells, compared to other cell types. This proposal seeks to solve this long-standing question.
描述(由申请人提供):mTOR是一种普遍表达的丝氨酸/苏氨酸激酶。mTOR酶存在于两个细胞复合物TORC1和TORC2中。mTOR是根据它与药物雷帕霉素的相互作用而被发现和命名的。该化合物是一种变构抑制剂,部分阻断TORC1活性,通常不抑制TORC2功能。雷帕霉素治疗T淋巴细胞和B淋巴细胞可深刻阻断抗原和其他有丝分裂原引发的增殖,雷帕霉素(西罗莫司;Rapamune(R))是fda批准的免疫抑制剂。然而,雷帕霉素及其类似物对包括癌细胞在内的其他细胞系统的增殖作用较小。尽管雷帕霉素对淋巴细胞的影响已经研究了20年,但仍不清楚为什么这种化合物在淋巴细胞中选择性地诱导了严重的增殖阻滞。矛盾的是,一类新的atp竞争性mTOR激酶抑制剂(TOR-KIs)比雷帕霉素引起的免疫抑制更小,尽管对TORC1和TORC2都有更完全的抑制。该项目的目标是确定雷帕霉素选择性阻断正常淋巴细胞增殖的机制。在初步数据的基础上,我们提出了两个假设,它们构成了不同具体目标的基础。目的1将验证雷帕霉素对S6激酶(TORC1的关键底物)的抑制更完全和持续的假设。有两种S6激酶,S6K1和S6K2,但它们在淋巴细胞活化和增殖中的作用尚未报道。我们将使用一种新的小鼠模型,该模型将允许化学遗传方法特异性抑制正常T细胞和B细胞中的S6K活性。我们将使用该模型来比较S6K抑制与雷帕霉素和TOR-KIs的作用。目的2将检验雷帕霉素抑制mTOR激酶无关功能的假设。我们将产生一种新的小鼠品系,其中激酶死亡的mTOR可以以细胞特异性的方式表达。这将使我们能够验证表达激酶死亡mTOR的淋巴细胞将保留对雷帕霉素敏感的残余增殖的预测。我们还将开始一种候选方法来测试可能的激酶无关mTOR功能。

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 }}

DAVID Alexander FRUMAN其他文献

DAVID Alexander FRUMAN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('DAVID Alexander FRUMAN', 18)}}的其他基金

Repurposing statins to enhance efficacy of BCL-2 antagonists in blood cancer
重新利用他汀类药物以增强 BCL-2 拮抗剂治疗血癌的疗效
  • 批准号:
    9178942
  • 财政年份:
    2016
  • 资助金额:
    $ 19.19万
  • 项目类别:
Repurposing statins to enhance efficacy of BCL-2 antagonists in blood cancer
重新利用他汀类药物以增强 BCL-2 拮抗剂治疗血癌的疗效
  • 批准号:
    9316613
  • 财政年份:
    2016
  • 资助金额:
    $ 19.19万
  • 项目类别:
Regulation of B cell differentiation by eIF4E
eIF4E 对 B 细胞分化的调节
  • 批准号:
    9244731
  • 财政年份:
    2016
  • 资助金额:
    $ 19.19万
  • 项目类别:
Combination strategies to enhance therapy for Ph-like B-ALL
增强 Ph 样 B-ALL 治疗的联合策略
  • 批准号:
    8912208
  • 财政年份:
    2015
  • 资助金额:
    $ 19.19万
  • 项目类别:
UCI-GPS: UC Irvine Graduate Professional Success
UCI-GPS:加州大学欧文分校毕业生职业成功
  • 批准号:
    9341983
  • 财政年份:
    2014
  • 资助金额:
    $ 19.19万
  • 项目类别:
UCI-GPS: UC Irvine Graduate Professional Success
UCI-GPS:加州大学欧文分校毕业生职业成功
  • 批准号:
    8929336
  • 财政年份:
    2014
  • 资助金额:
    $ 19.19万
  • 项目类别:
UCI-GPS: UC Irvine Graduate Professional Success
UCI-GPS:加州大学欧文分校毕业生职业成功
  • 批准号:
    8829529
  • 财政年份:
    2014
  • 资助金额:
    $ 19.19万
  • 项目类别:
TOR kinase inhibitors for leukemia therapy: mechanisms of action and resistance
用于白血病治疗的 TOR 激酶抑制剂:作用机制和耐药性
  • 批准号:
    8628792
  • 财政年份:
    2012
  • 资助金额:
    $ 19.19万
  • 项目类别:
Solving the elusive mechanism of rapamycin action in lymphocytes
解决雷帕霉素在淋巴细胞中作用的难以捉摸的机制
  • 批准号:
    8531852
  • 财政年份:
    2012
  • 资助金额:
    $ 19.19万
  • 项目类别:
TOR kinase inhibitors for leukemia therapy: mechanisms of action and resistance
用于白血病治疗的 TOR 激酶抑制剂:作用机制和耐药性
  • 批准号:
    8815271
  • 财政年份:
    2012
  • 资助金额:
    $ 19.19万
  • 项目类别:

相似海外基金

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:
    $ 19.19万
  • 项目类别:
    Training 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:
    $ 19.19万
  • 项目类别:
    Standard Grant
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:
    $ 19.19万
  • 项目类别:
    Standard 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:
    $ 19.19万
  • 项目类别:
    Fellowship
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:
    $ 19.19万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
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:
    $ 19.19万
  • 项目类别:
    Research Grant
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:
    $ 19.19万
  • 项目类别:
    Studentship
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:
    $ 19.19万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 19.19万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 19.19万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了