Parameters that determine cell fate during mitotic arrest
有丝分裂停滞期间决定细胞命运的参数
基本信息
- 批准号:10409136
- 负责人:
- 金额:$ 14.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-10 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:4D ImagingAddressAdjuvant TherapyAntimitotic AgentsApoptosisApoptoticBCL2 geneBiochemicalBiosensorCancer cell lineCell CycleCell DeathCell LineCell SurvivalCell divisionCellsCentriolesChromosome SegregationClinicDataDependenceDrug resistanceExhibitsFailureFamilyFlow CytometryFoundationsFutureGoalsGrowthHela CellsHeterogeneityHormonesImageIndividualJordanKinesinKineticsLaboratoriesMCL1 geneMalignant NeoplasmsMetabolismMicroscopyMicrotubulesMitosisMitoticMitotic spindleMolecularMolecular MotorsNormal CellPathway interactionsPeripheral Nervous System DiseasesPharmaceutical PreparationsPhosphotransferasesProtein InhibitionProteinsReagentRegulationRegulatory PathwayResolutionRoleSignal PathwaySignal TransductionStructureTP53 geneTimeVinblastineVinca AlkaloidsWestern BlottingWorkYangbasecancer cellcancer therapycell behaviorchemotherapydrug developmentgraduate studentimaging approachinhibitorinsightlive cell imagingmTOR Signaling Pathwaymemberneoplastic cellpopulation basedresponseside effecttaxanetraining opportunitytranslational studytumorundergraduate student
项目摘要
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.
有丝分裂纺锤体断裂导致纺锤体组装检查点(SAC)延长激活
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)
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Charles Bradley Shuster其他文献
Charles Bradley Shuster的其他文献
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{{ truncateString('Charles Bradley Shuster', 18)}}的其他基金
Parameters that determine cell fate during mitotic arrest
有丝分裂停滞期间决定细胞命运的参数
- 批准号:
10617385 - 财政年份:2022
- 资助金额:
$ 14.4万 - 项目类别:
Parameters that determine cell fate during mitotic arrest
有丝分裂停滞期间决定细胞命运的参数
- 批准号:
10797794 - 财政年份:2022
- 资助金额:
$ 14.4万 - 项目类别:
Spindle orientation along the developmental axes in echinoderm embryos
棘皮动物胚胎沿发育轴的纺锤体方向
- 批准号:
8733008 - 财政年份:2014
- 资助金额:
$ 14.4万 - 项目类别:
DEVELOPMENT OF NOVEL SMALL MOLECULE INHIBITORS OF AURORA B KINASE SIGNALING
新型 AURORA B 激酶信号传导小分子抑制剂的开发
- 批准号:
8359753 - 财政年份:2011
- 资助金额:
$ 14.4万 - 项目类别:
DEVELOPMENT OF NOVEL SMALL MOLECULE INHIBITORS OF AURORA B KINASE SIGNALING
新型 AURORA B 激酶信号传导小分子抑制剂的开发
- 批准号:
8167576 - 财政年份:2010
- 资助金额:
$ 14.4万 - 项目类别:
Mob1 Localization and Function During Mitosis
Mob1 在有丝分裂期间的定位和功能
- 批准号:
8292148 - 财政年份:2009
- 资助金额:
$ 14.4万 - 项目类别:
Mob1 Localization and Function During Mitosis
Mob1 在有丝分裂期间的定位和功能
- 批准号:
7904769 - 财政年份:2009
- 资助金额:
$ 14.4万 - 项目类别:
CHARACTERIZATION OF MOB1 DYNAMICS IN LIVING CELLS
活细胞中 MOB1 动力学的表征
- 批准号:
7960229 - 财政年份:2009
- 资助金额:
$ 14.4万 - 项目类别:
Mob1 Localization and Function During Mitosis
Mob1 在有丝分裂期间的定位和功能
- 批准号:
8070024 - 财政年份:2009
- 资助金额:
$ 14.4万 - 项目类别:
Mob1 Localization and Function During Mitosis
Mob1 在有丝分裂期间的定位和功能
- 批准号:
7628920 - 财政年份:2009
- 资助金额:
$ 14.4万 - 项目类别:
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