Telomerase-Mediated Healing of Double-Strand Breaks in Human Cells
端粒酶介导的人体细胞双链断裂修复
基本信息
- 批准号:10560471
- 负责人:
- 金额:$ 5.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AneuploidyApoptosisAwardBase PairingBindingBiological AssayCell AgingCell SurvivalCell divisionCellsCentromereChromosomal BreaksChromosome 16Chromosome DeletionChromosomesClinicalComplexDNA DamageDNA Double Strand BreakDNA PrimaseDataDevelopmentDicentric chromosomeDistalDoctor of PhilosophyDouble Strand Break RepairDoxycyclineEctopic ExpressionEnvironmentEventFrequenciesGenesGenomeGenome StabilityGenomic InstabilityGenomicsGerm CellsGoalsGonadal structureHaploidyHela CellsHumanIn VitroInstitutionLengthLinkMalignant NeoplasmsMediatingMedicalMethodsMolecularNeoplasmsPathologicPathway interactionsPatient CarePatientsPhysiciansPhysiologicalPolymeraseProcessProliferatingRegulationReporterRepressionRoleRunningRuptureScientistSignal TransductionSomatic CellTP53 geneTelomeraseTelomerase InhibitorTelomerase RNA ComponentTelomerase inhibitionTelomere MaintenanceTelomere ShorteningTestingTreesalpha-Thalassemiacancer cellcancer diagnosiscancer preventioncarcinogenesiscareercell transformationchromosome fusionchromothripsisdesigndetection assayexpectationexperimental studygenetic approachhealingimprovedmortalityneoplastic cellnovel strategiesp53-binding protein 1preventprogramsreconstitutionrecruitrepairedresponsesenescencestem cellstelomeretumortumorigenesis
项目摘要
PROJECT SUMMARY/ABSTRACT
Telomeres—which define and protect the ends of humans’ linear chromosomes—serve as a natural check on
carcinogenesis. Genome stability requires cells to differentiate telomeres from perilous DNA double-strand
breaks (DSBs) to block inappropriate DSB repair and DNA damage response (DDR) signaling, which humans
accomplish with the shelterin complex. Telomerase maintains telomere length in the gonads and some stem
cells, but telomeres in somatic cells shorten with each cell division due to developmental silencing of
telomerase. Unfettered cell division in early neoplasms eventually leads to a few telomeres becoming critically
short and activating persistent DDR signaling, which causes cells with functional p53 and Rb pathways to
undergo senescence or apoptosis. Cells defective in these pathways continue to divide until multiple telomeres
become de-protected and then enter telomere crisis, defined by poor cell viability due to intolerable genomic
instability, as chromosomes repeatedly fuse at their ends and break. Clinical tumors emerge from crisis with
rearranged, aneuploid genomes and a telomere maintenance mechanism. To escape from telomere crisis, I
predict that malignant cells must reconstitute their telomeres and that telomerase may accomplish this by
directly repairing non-telomeric chromosome ends with neotelomeres.
The objective of the proposed project is to identify and mechanistically characterize telomerase-
mediated DSB repair in human cells. In vitro, telomerase can add TTAGGG repeats to a non-telomeric
breakpoint sequence derived from a patient with α-thalassemia due to a terminal chromosomal truncation.
Using this sequence, I have designed a PCR-based reporter assay to detect neotelomere formation in cells at
an inducible DSB and have gathered evidence that suggests that telomere healing occurs in human cells in a
telomerase-dependent manner. I will improve this assay with TaqMan probes on a qPCR platform to rigorously
quantify telomere healing events and will perform further experiments to demonstrate that telomerase is
responsible for TTAGGG repeat addition. Because telomerase-mediated repair threatens to convert DSBs into
terminal chromosome deletions, I hypothesize that human cells have evolved mechanisms to block telomerase
activity at DSBs. I will implement a genetic approach with my telomere healing assay to identify the physiologic
repressors of this aberrant mode of DSB repair. Ultimately, I aim to unveil a new role for telomerase in enabling
incipient cancers to traverse the bottleneck of telomere crisis. This leap in our understanding of genomic
instability in early tumorigenesis may lead to unexpected ways to detect and prevent cancer in patients. With
the aid of this award and the stimulating environment of the Tri-Institutional MD/PhD Program, I will grow
scientifically, medically, and professionally in ways that will enable me to advance toward my long-term career
goal of leading a cancer-centric lab while providing patient care as a transformative physician-scientist.
项目概要/摘要
端粒——定义并保护人类线性染色体的末端——作为一种自然检查
致癌作用。基因组稳定性需要细胞将端粒与危险的 DNA 双链区分开来
断裂(DSB)以阻止不适当的 DSB 修复和 DNA 损伤反应(DDR)信号传导,人类
通过庇护所完成。端粒酶维持性腺和某些茎中端粒的长度
细胞,但体细胞中的端粒随着每次细胞分裂而缩短,这是由于
端粒酶。早期肿瘤中不受限制的细胞分裂最终导致一些端粒变得至关重要
短且激活持续的 DDR 信号传导,导致具有功能性 p53 和 Rb 途径的细胞
经历衰老或凋亡。这些途径有缺陷的细胞继续分裂,直到形成多个端粒
失去保护,然后进入端粒危机,其定义是由于无法耐受的基因组导致细胞活力较差
不稳定,因为染色体在末端反复融合和断裂。临床肿瘤摆脱危机
重新排列的非整倍体基因组和端粒维持机制。为了摆脱端粒危机,我
预测恶性细胞必须重建它们的端粒,而端粒酶可以通过以下方式实现这一点
用新端粒直接修复非端粒染色体末端。
拟议项目的目标是识别端粒酶并对其进行机械表征
介导人类细胞中的 DSB 修复。在体外,端粒酶可以将 TTAGGG 重复序列添加到非端粒上
断点序列源自因染色体末端截断而患有 α 地中海贫血的患者。
利用这个序列,我设计了一种基于 PCR 的报告基因检测方法来检测细胞中新端粒的形成
一种诱导型 DSB,并收集了证据表明端粒愈合发生在人类细胞中
端粒酶依赖性方式。我将在 qPCR 平台上使用 TaqMan 探针改进该测定,以严格
量化端粒愈合事件并将进行进一步的实验来证明端粒酶
负责 TTAGGG 重复添加。因为端粒酶介导的修复有可能将 DSB 转化为
末端染色体缺失,我假设人类细胞已经进化出阻断端粒酶的机制
DSB 的活动。我将通过我的端粒愈合测定实施遗传方法来识别生理学
这种 DSB 修复异常模式的抑制因子。最终,我的目标是揭示端粒酶在使
早期癌症跨越端粒危机的瓶颈。我们对基因组理解的飞跃
早期肿瘤发生的不稳定性可能会导致意想不到的方法来检测和预防患者的癌症。和
在这个奖项的帮助和三机构医学博士/博士项目的激励环境下,我会成长
科学、医学和专业的方式使我能够朝着我的长期职业生涯前进
目标是领导一个以癌症为中心的实验室,同时作为变革性的医生科学家为患者提供护理。
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 }}
Charles Gunnar Kinzig其他文献
Charles Gunnar Kinzig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('Charles Gunnar Kinzig', 18)}}的其他基金
Telomerase-Mediated Healing of Double-Strand Breaks in Human Cells
端粒酶介导的人体细胞双链断裂修复
- 批准号:
10321890 - 财政年份:2021
- 资助金额:
$ 5.27万 - 项目类别:
相似国自然基金
Epac1/2通过蛋白酶体调控中性粒细胞NETosis和Apoptosis在急性肺损伤中的作用研究
- 批准号:LBY21H010001
- 批准年份:2020
- 资助金额:0.0 万元
- 项目类别:省市级项目
基于Apoptosis/Ferroptosis双重激活效应的天然产物AlbiziabiosideA的抗肿瘤作用机制研究及其结构改造
- 批准号:81703335
- 批准年份:2017
- 资助金额:20.0 万元
- 项目类别:青年科学基金项目
双肝移植后Apoptosis和pyroptosis在移植物萎缩差异中的作用和供受者免疫微环境变化研究
- 批准号:81670594
- 批准年份:2016
- 资助金额:58.0 万元
- 项目类别:面上项目
Serp-2 调控apoptosis和pyroptosis 对肝脏缺血再灌注损伤的保护作用研究
- 批准号:81470791
- 批准年份:2014
- 资助金额:73.0 万元
- 项目类别:面上项目
Apoptosis signal-regulating kinase 1是七氟烷抑制小胶质细胞活化的关键分子靶点?
- 批准号:81301123
- 批准年份:2013
- 资助金额:23.0 万元
- 项目类别:青年科学基金项目
APO-miR(multi-targeting apoptosis-regulatory miRNA)在前列腺癌中的表达和作用
- 批准号:81101529
- 批准年份:2011
- 资助金额:22.0 万元
- 项目类别:青年科学基金项目
放疗与细胞程序性死亡(APOPTOSIS)相关性及其应用研究
- 批准号:39500043
- 批准年份:1995
- 资助金额:9.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Development of an apoptosis biosensor for monitoring of breast cancer
开发用于监测乳腺癌的细胞凋亡生物传感器
- 批准号:
10719415 - 财政年份:2023
- 资助金额:
$ 5.27万 - 项目类别:
Milk fat globule-EGF factor 8 and hepatocyte apoptosis-induced liver wound healing response
乳脂肪球-EGF因子8与肝细胞凋亡诱导的肝脏创面愈合反应
- 批准号:
10585802 - 财政年份:2023
- 资助金额:
$ 5.27万 - 项目类别:
Interrogating the Fgl2-FcγRIIB axis on CD8+ T cells: A novel mechanism mediating apoptosis of tumor-specific memory CD8+ T cells
询问 CD8 T 细胞上的 Fgl2-FcγRIIB 轴:介导肿瘤特异性记忆 CD8 T 细胞凋亡的新机制
- 批准号:
10605856 - 财政年份:2023
- 资助金额:
$ 5.27万 - 项目类别:
Novel targeted therapy for FGFR inhibitor-resistant urothelial cancer and apoptosis based therapy for urothelial cancer
FGFR抑制剂耐药性尿路上皮癌的新型靶向治疗和基于细胞凋亡的尿路上皮癌治疗
- 批准号:
23K08773 - 财政年份:2023
- 资助金额:
$ 5.27万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Mechanistic analysis of apoptosis induction by HDAC inhibitors in head and neck cancer
HDAC抑制剂诱导头颈癌凋亡的机制分析
- 批准号:
23K15866 - 财政年份:2023
- 资助金额:
$ 5.27万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Interrogating the Fgl2-FcgRIIB axis: A novel mechanism mediating apoptosis of tumor-specific memory CD8+ T cells
探究 Fgl2-FcgRIIB 轴:介导肿瘤特异性记忆 CD8 T 细胞凋亡的新机制
- 批准号:
10743485 - 财政年份:2023
- 资助金额:
$ 5.27万 - 项目类别:
Investigating the role of apoptosis-resistance and the tumor environment on development and maintenance of sacrococcygeal teratomas
研究细胞凋亡抗性和肿瘤环境对骶尾部畸胎瘤发生和维持的作用
- 批准号:
10749797 - 财政年份:2023
- 资助金额:
$ 5.27万 - 项目类别:
The effects of glucose on immune cell apoptosis and mitochondrial membrane potential and the analysis of its mechanism by which glucose might modulate the immune functions.
葡萄糖对免疫细胞凋亡和线粒体膜电位的影响及其调节免疫功能的机制分析。
- 批准号:
22K09076 - 财政年份:2022
- 资助金额:
$ 5.27万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
XAF1 IN P53 SIGNALING, APOPTOSIS AND TUMOR SUPPRESSION
P53 信号传导、细胞凋亡和肿瘤抑制中的 XAF1
- 批准号:
10583516 - 财政年份:2022
- 资助金额:
$ 5.27万 - 项目类别:
Role of Thioredoxin system in regulation of autophagy-apoptosis cross talk in neurons: Uncovering Novel Molecular Interactions.
硫氧还蛋白系统在神经元自噬-凋亡串扰调节中的作用:揭示新的分子相互作用。
- 批准号:
RGPIN-2019-05371 - 财政年份:2022
- 资助金额:
$ 5.27万 - 项目类别:
Discovery Grants Program - Individual














{{item.name}}会员




