Parameters that determine cell fate during mitotic arrest
Parameters that determine cell fate during mitotic arrest
批准号:
10797794
负责人:
Charles Bradley Shuster
金额:
$10.0万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-05-10 至 2026-03-31
关键词:
4D ImagingAccelerationAdjuvant TherapyAntimitotic AgentsApoptosisBiochemicalCell DeathCell LineCell SurvivalCell divisionCellsCentriolesChromosome SegregationClinicDataDependenceFoundationsFutureGrowthHeterogeneityHormonesImageKinesinKineticsMalignant NeoplasmsMetabolismMicrotubulesMitosisMitoticMitotic spindleMolecular MotorsNormal CellPharmaceutical PreparationsPhosphotransferasesProliferatingProteinsRegulatory PathwayResolutionRoleSignal PathwaySignal TransductionStructureTP53 geneTherapeuticVinblastinecancer cellimaging approachlive cell imagingmTOR Signaling Pathwayneoplastic cellresponseside effecttranslational study
中文摘要
有丝分裂纺锤体中断导致纺锤体组装检查点(SAC)激活时间延长
可导致P53激活、中心粒脱离和细胞死亡。事实上,有一个
化疗策略经常应用于侵袭性和激素非依赖性癌症
是以有丝分裂纺锤体为靶点,这是一种基于微管的结构,是正常发育所必需的
染色体分离和细胞分裂。长春花碱或紫杉醇等药物可抑制
正常的微管组装动力学,导致有丝分裂停止和最终细胞死亡,通过
细胞凋亡。然而,尽管它们在临床上实施了几十年,但通过
哪种延长的有丝分裂延迟导致细胞死亡尚不清楚。此外,尽管
有丝分裂纺锤体对细胞分裂的普遍要求,目前仍有大量
细胞对纺锤体破坏的反应方式的异质性,这可能会降低抗
有丝分裂化疗策略。使用生化和活细胞成像的组合
方法,我们的初步数据显示,靶向两个运动蛋白纺锤体蛋白(KSP),一个
纺锤体双极性所需的分子马达和磷脂酰肌醇3-激酶
(PI3K)/Akt/mTor信号通路显著加速有丝分裂细胞死亡的动力学
相对于有丝分裂停滞而言。此外,它还引起了来自
处理过的细胞。PI3K信号参与多种调节细胞的调节通路
生存、代谢和增殖,但PI3K活性促进细胞的机制
有丝分裂停滞期间的存活率尚不清楚。为了更好地了解PI3K信号是如何参与
细胞死亡的时间和细胞有丝分裂反应的变异性,我们将继续
应用高通量时间流逝成像、高分辨率4D成像和生化
细胞系电池的方法不同于它们对有丝分裂延迟的敏感性以及
依赖于PI3K信号。该项目的具体目标将1)定义保护
PI3K在正常细胞和癌细胞中的作用;以及2)决定PI3K的机制
在有丝分裂延迟期间促进细胞存活。如果成功,这些研究将为
未来的翻译研究将进一步开发针对有丝分裂活性的辅助疗法
无其他微管干扰物副作用的肿瘤细胞。
英文摘要
Prolonged activation of the spindle assembly checkpoint (SAC) due to mitotic spindle disruption
can result in p53 activation, centriole disengagement and cell death. Indeed, one
chemotherapeutic strategy frequently applied to aggressive and hormone-independent cancers
is to target the mitotic spindle, a microtubule-based structure that is required for proper
chromosome segregation and cell division. Drugs such as vinblastine or Paciltaxel suppress the
normal microtubule assembly dynamics, leading to mitotic arrest and eventual cell death by
apoptosis. However, despite their decades-long implementation in the clinic, the mechanisms by
which prolonged mitotic delay results in cell death remains unclear. Further, despite the
universality of the requirement of the mitotic spindle for cell division, there is still a great deal of
heterogeneity in how cells respond to spindle disruption, which may reduce the efficacy of anti-
mitotic chemotherapeutic strategies. Using a combination of biochemical and live cell imaging
approaches, our preliminary data reveals that targeting both Kinesin Spindle Protein (KSP), a
molecular motor required for spindle bipolarity, and the Phosphatidylinositide 3-kinase
(PI3K)/Akt/mTOR signaling pathway dramatically accelerates the kinetics of mitotic cell death
relative to mitotic arrest alone. Moreover, it elicits a more homogeneous response from the
treated cells. PI3K signaling is involved in a variety of regulatory pathways that regulate cell
survival, metabolism and proliferation, but the mechanism by which PI3K activity promotes cell
viability during mitotic arrest is unknown. To better understand how PI3K signaling is involved in
the timing of cell death and variability of cellular responses of mitotic delay, we will continue to
apply high-throughput timelapse imaging, high-resolution 4D imaging and biochemical
approaches to a battery of cell lines differ in their sensitivity to mitotic delay as well as
dependence on PI3K signaling. The Specific Aims of this project will 1) Define the protective
role of PI3K in normal and cancer cells; and 2) Determine the mechanism by which PI3K
promotes cell survival during mitotic delay. If successful, these studies will lay the foundation for
future translational studies to further develop adjuvant therapies that will target mitotically active
tumor cells without the side effects associated with other microtubule disruptors.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Parameters that determine cell fate during mitotic arrest
-
批准号:10617385
-
项目类别:
-
资助金额:$14.4万
-
财政年份:2022
-
负责人:Charles Bradley Shuster
-
依托单位:
Parameters that determine cell fate during mitotic arrest
-
批准号:10409136
-
项目类别:
-
资助金额:$14.4万
-
财政年份:2022
-
负责人:Charles Bradley Shuster
-
依托单位:
Spindle orientation along the developmental axes in echinoderm embryos
-
批准号:8733008
-
项目类别:
-
资助金额:$42.65万
-
财政年份:2014
-
负责人:Charles Bradley Shuster
-
依托单位:
DEVELOPMENT OF NOVEL SMALL MOLECULE INHIBITORS OF AURORA B KINASE SIGNALING
-
批准号:8359753
-
项目类别:
-
资助金额:$10.74万
-
财政年份:2011
-
负责人:Charles Bradley Shuster
-
依托单位:
DEVELOPMENT OF NOVEL SMALL MOLECULE INHIBITORS OF AURORA B KINASE SIGNALING
-
批准号:8167576
-
项目类别:
-
资助金额:$10.85万
-
财政年份:2010
-
负责人:Charles Bradley Shuster
-
依托单位:
Mob1 Localization and Function During Mitosis
-
批准号:8292148
-
项目类别:
-
资助金额:$24.22万
-
财政年份:2009
-
负责人:Charles Bradley Shuster
-
依托单位:
Mob1 Localization and Function During Mitosis
-
批准号:7904769
-
项目类别:
-
资助金额:$24.86万
-
财政年份:2009
-
负责人:Charles Bradley Shuster
-
依托单位:
CHARACTERIZATION OF MOB1 DYNAMICS IN LIVING CELLS
-
批准号:7960229
-
项目类别:
-
资助金额:$12.87万
-
财政年份:2009
-
负责人:Charles Bradley Shuster
-
依托单位:
Mob1 Localization and Function During Mitosis
-
批准号:8070024
-
项目类别:
-
资助金额:$24.22万
-
财政年份:2009
-
负责人:Charles Bradley Shuster
-
依托单位:
Mob1 Localization and Function During Mitosis
-
批准号:7628920
-
项目类别:
-
资助金额:$24.25万
-
财政年份:2009
-
负责人:Charles Bradley Shuster
-
依托单位:
CHARACTERIZATION OF MOB1 DYNAMICS IN LIVING CELLS
-
批准号:7720454
-
项目类别:
-
资助金额:$12.62万
-
财政年份:2008
-
负责人:Charles Bradley Shuster
-
依托单位:
CHARACTERIZATION OF MOB1 DYNAMICS IN LIVING CELLS
-
批准号:7610365
-
项目类别:
-
资助金额:$4.21万
-
财政年份:2007
-
负责人:Charles Bradley Shuster
-
依托单位:
CHARACTERIZATION OF MOB1 DYNAMICS IN LIVING CELLS
-
批准号:7381754
-
项目类别:
-
资助金额:$4.3万
-
财政年份:2006
-
负责人:Charles Bradley Shuster
-
依托单位:
CHARACTERIZATION OF MOB1 DYNAMICS IN LIVING CELLS
-
批准号:7170974
-
项目类别:
-
资助金额:$4.51万
-
财政年份:2005
-
负责人:Charles Bradley Shuster
-
依托单位:
Coordination of Mitotsis and Cytokinesis in Animal Cells
-
批准号:6766198
-
项目类别:
-
资助金额:$21.59万
-
财政年份:2004
-
负责人:Charles Bradley Shuster
-
依托单位:
SIGNALING PATHWAYS AND CYTOKINESIS
-
批准号:2684663
-
项目类别:
-
资助金额:$3.02万
-
财政年份:1998
-
负责人:Charles Bradley Shuster
-
依托单位:
SIGNALING PATHWAYS AND CYTOKINESIS
-
批准号:2900469
-
项目类别:
-
资助金额:$1.92万
-
财政年份:1997
-
负责人:Charles Bradley Shuster
-
依托单位:
SIGNALING PATHWAYS AND CYTOKINESIS
-
批准号:2021600
-
项目类别:
-
资助金额:$2.54万
-
财政年份:1997
-
负责人:Charles Bradley Shuster
-
依托单位:
Coordination of Mitotsis and Cytokinesis in Animal Cells
-
批准号:7448506
-
项目类别:
-
资助金额:$25.83万
-
财政年份:--
-
负责人:Charles Bradley Shuster
-
依托单位:
Coordination of Mitotsis and Cytokinesis in Animal Cells
-
批准号:7244346
-
项目类别:
-
资助金额:$12.08万
-
财政年份:--
-
负责人:Charles Bradley Shuster
-
依托单位:
海外基金