Defining the DNA damage pathway in faithful mitotic progression
定义忠实有丝分裂进展中的 DNA 损伤途径
基本信息
- 批准号:10415991
- 负责人:
- 金额:$ 18.62万
- 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:2020-06-02 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:ATR geneAffectAneuploidyAwardBindingBreast cancer metastasisCancer BiologyCancer ModelCancer cell lineCell Cycle ArrestCell LineCellsCellular biologyCentromereCessation of lifeChromosomal InstabilityChromosome SegregationChromosomesCongenital AbnormalityDNA DamageDNA RepairDNA biosynthesisDefectDiploidyDrug resistanceEnsureEventExhibitsGenetic MaterialsGenetic VariationGenome StabilityGenomic InstabilityGoalsHematologic NeoplasmsImmuneImmune EvasionInstitutionInterphaseKaryotypeLeadLinkMalignant NeoplasmsMalignant neoplasm of ovaryMass Spectrum AnalysisMediator of activation proteinMitosisMitoticMusNeoplasm MetastasisOrganismPathway interactionsPhenotypePhosphotransferasesPopulationPositioning AttributeProcessProteinsPublishingResearchResearch PersonnelRoleS phaseSingle-Stranded DNASiteSolid NeoplasmTest ResultTestingTherapeuticTimeTumorigenicitycancer cellcancer therapycareerchemotherapychromosome missegregationeffective therapyfaculty researchinhibitormalignant breast neoplasmmouse modelneoplastic cellnovelpatient prognosispreventrecruitreplication stressresponsesegregationskillssuccesstargeted cancer therapytherapy resistanttumortumor progression
项目摘要
PROJECT SUMMARY/ABSTRACT
Genomic instability is a hallmark of cancer and correlated with overall poor patient prognosis. A specific
form of genomic instability is chromosomal instability (CIN), which occurs when a cell continuously missegregate
their chromosomes leading to changes in karyotype. CIN is a common feature of cancer – with approximately
90% of solid tumors and 50% of hematopoietic cancers exhibiting CIN. CIN is also correlated with increased
tumor progression and poor patient prognosis. However, the levels of CIN must be maintained at an optimal
level, because too high levels of missegregation events are deleterious to cells. This creates a therapeutic
window by which chemotherapies can exploit CIN to create effective treatments against cancer cells. ATR, a
master regulator of DNA damage repair pathways, ensures genomic stability by promoting DNA damage repair
and timely replication. I recently showed that ATR also promotes genomic stability by promoting faithful
chromosome segregation in mitosis and preventing CIN. In this application, I propose to investigate the
mechanism by which ATR is activated in mitosis (Aim 1), identify its substrate network (Aim 2) and use ATR
inhibition to target CIN cancer cells specifically (Aim 3). My proposed studies may reveal more novel functions
of ATR in mitosis and allow us to better understand of how mitotic processes are regulated by ATR and other
DDR proteins to ensure proper chromosome segregation. This in turn, will give us a better understanding of the
overlap of mitotic and DDR proteins in ensuring genomic stability. Lastly, I hope that developing a strategy to
specifically kill CIN cancer cells will be a breakthrough in targeted cancer therapies.
My career goal is to obtain a research faculty position at a leading institution where I will dissect the
mechanisms by which ATR and other DDR proteins regulate chromosome segregation. My successful transition
would be bolstered by augmenting my expertise in cell biology, mass spectrometry and mouse cancer models.
I will use these acquired skills to investigate whether ATR inhibitors can be used to specifically target CIN cancer
cells. Importantly, the protected time that this award provides me will allow me to elucidate the mechanism by
which ATR is activated and determine if ATR inhibitors can be used to exploit CIN in cancer cells. Furthermore,
the success of this project will be greatly enhanced by the outstanding collaborators that I will have advise me
through the K22 period. The receipt of this award will allow me to expand my research plan and establish myself
as a primary investigator in the field of cancer biology.
项目摘要/摘要
基因组不稳定是癌症的一个标志,与患者总体预后不良有关。一种特定的
基因组不稳定的形式是染色体不稳定(CIN),当一个细胞连续错误分离时就会发生
他们的染色体导致了核型的变化。宫颈上皮内瘤变是癌症的常见特征--大约
90%的实体瘤和50%的血液癌表现为CIN。CIN也与增加的
肿瘤进展和患者预后不良。然而,CIN水平必须保持在最佳水平
水平,因为太高水平的错误分离事件对细胞有害。这创造了一种治疗
化疗可以利用CIN创造针对癌细胞的有效治疗方法的窗口。ATR,a
掌握DNA损伤修复途径的调节者,通过促进DNA损伤修复来确保基因组的稳定性
和及时复制。我最近发现,ATR还通过促进忠诚来促进基因组稳定性
有丝分裂中的染色体分离与CIN的预防。在此应用程序中,我建议调查
ATR在有丝分裂中被激活的机制(目标1),鉴定其底物网络(目标2)并使用ATR
对CIN癌细胞的特异性抑制(目标3)。我提出的研究可能会揭示更多新的功能
研究ATR在有丝分裂中的作用,使我们能够更好地理解ATR和其他
DDR蛋白质,以确保适当的染色体分离。这反过来又会让我们更好地理解
有丝分裂和DDR蛋白在确保基因组稳定性方面的重叠。最后,我希望制定一项战略来
特异地杀死CIN癌细胞将是靶向癌症治疗的一个突破。
我的职业目标是在一家领先的机构获得一个研究教员的职位,在那里我将剖析
ATR和其他DDR蛋白调节染色体分离的机制。我的成功过渡
通过增加我在细胞生物学、质谱学和老鼠癌症模型方面的专业知识,将会得到支持。
我将利用这些获得的技能来研究ATR抑制剂是否可以专门针对CIN癌症
细胞。重要的是,这一裁决提供的保护时间将使我能够通过
哪些ATR被激活,并确定ATR抑制剂是否可以用于开发癌细胞中的CIN。此外,
我将得到的杰出合作者的建议将大大加强这个项目的成功
在K22时期。获得这一奖项将使我能够扩大我的研究计划并确立自己的地位
作为癌症生物学领域的主要研究员。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
ATR promotes clearance of damaged DNA and damaged cells by rupturing micronuclei.
- DOI:10.1016/j.molcel.2023.09.003
- 发表时间:2023-09
- 期刊:
- 影响因子:16
- 作者:Yoon Ki Joo;Elizabeth M. Black;Isabelle Trier;W. Haakma;Lee Zou;Lilian Kabeche
- 通讯作者:Yoon Ki Joo;Elizabeth M. Black;Isabelle Trier;W. Haakma;Lee Zou;Lilian Kabeche
{{
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 }}
Lilian Carolina Kabeche其他文献
Lilian Carolina Kabeche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('Lilian Carolina Kabeche', 18)}}的其他基金
Elucidating how ATR promotes genome stability independent of the DNA damage response pathway
阐明 ATR 如何独立于 DNA 损伤反应途径促进基因组稳定性
- 批准号:
10711931 - 财政年份:2023
- 资助金额:
$ 18.62万 - 项目类别:
Defining the DNA damage pathway in faithful mitotic progression
定义忠实有丝分裂进展中的 DNA 损伤途径
- 批准号:
10177975 - 财政年份:2020
- 资助金额:
$ 18.62万 - 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:
$ 18.62万 - 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:
$ 18.62万 - 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:
$ 18.62万 - 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:
$ 18.62万 - 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:
$ 18.62万 - 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:
$ 18.62万 - 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:
$ 18.62万 - 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:
$ 18.62万 - 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:
$ 18.62万 - 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:
$ 18.62万 - 项目类别:
Grant-in-Aid for Early-Career Scientists














{{item.name}}会员




