DNA Damage Responses in B Cell Development
B 细胞发育中的 DNA 损伤反应
基本信息
- 批准号:7749036
- 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:2009
- 资助国家:美国
- 起止时间:2009-01-01 至 2012-12-31
- 项目状态:已结题
- 来源:
- 关键词:ATM geneATM wt AlleleAffectAntibodiesApoptosisAtaxia TelangiectasiaAttentionB-Cell DevelopmentB-Cell LymphomasB-Lymphocyte SubsetsB-LymphocytesBiological AssayCause of DeathCell LineageCellsChromatin StructureChromosomal translocationChromosome PairingColorDNADNA DamageDNA Double Strand BreakDNA RepairDNA SequenceDNA StructureDevelopmentDouble Strand Break RepairEventFluorescent in Situ HybridizationFrequenciesGene MutationGenerationsGenetic TranscriptionGenome StabilityHumanIGH@ gene clusterImmuneImmune responseImmunizationImmunoglobulin Class SwitchingImmunoglobulin Switch RecombinationImmunoglobulinsImmunohistochemistryIn VitroInduced MutationIonizing radiationLeadLymphoid CellMaintenanceMalignant NeoplasmsMalignant lymphoid neoplasmMature B-LymphocyteMethodsModelingMolecularMusOncogenicPathway interactionsPatientsPhysiologicalPopulationProcessProto-OncogenesReactionRecruitment ActivityRepair ComplexRoleSignal TransductionSingle-Stranded DNASiteStructure of germinal center of lymph nodeTechniquesTestingactivation-induced cytidine deaminasec-myc Genesin vivoinsightmembernovelprogramspublic health relevancerepairedresponsetherapeutic targettumorigenesis
项目摘要
DESCRIPTION (provided by applicant): B lineage cells of the immune are unique in their ability to undergo developmentally programmed DNA double strand breaks (DSB) within their immunoglobulin loci during an immune response in order to generate functional antibodies in a process termed class switch recombination (CSR). Switching B cells thus offer an excellent model to study cellular responses to physiologic DSB. B cells undergoing CSR trigger the DNA damage response (DDR) pathway, which signals cells to pause and repair DNA breaks, or if unable to resolve the damage to then undergo apoptosis. The DDR pathway is the initial cellular response to DNA damage, which is activated early in tumorigenesis but is frequently lost during progression to cancer. Disruption of the DDR pathway during CSR leads to impaired immunoglobulin switching in B cells and to chromosomal translocations involving the IgH locus. The ataxia-telangiectasia mutated gene (ATM) is the key coordinator of sensing and responding to DNA damage. B cells deficient for ATM have impaired CSR and frequently generate chromosomal translocations involving the immunoglobulin heavy chain locus. In this regard, ATM alterations have been detected in many lymphoid malignancies. The exact role of ATM in maintaining genomic stability in B lineage cells remains unknown. In this proposal we seek to develop methods to study the mechanisms that regulate ATM recruitment to programmed DNA breaks in B cells undergoing class switching. Localization and molecular assessment of the DSB repair complex will elucidate the components of the DDR during CSR. In addition we will examine defined populations of B cells participating in an active immune response to determine the specific populations in which ATM and other members of the DDR are recruited to the IgH locus. In our second aim, we will further test the exact DNA sequences that facilitate recruitment of ATM to the IgH locus. Taken together, these studies will further define the mechanisms that regulate the maintenance of genomic stability in ATM-deficient B cells, providing insights towards the development of therapeutic targets. PUBLIC HEALTH RELEVANCE: B cell lymphoma is a major cause of death in patients with ataxia-telangiectasia. The studies in this proposal seek to understand the basic mechanisms that promote oncogenic events B cells, which is also applicable towards other cancers that develop in AT patients. These findings may lead to the development of novel and rational therapeutic targets for cancer in patients with AT.
描述(由申请方提供):免疫的B谱系细胞在免疫应答期间在其免疫球蛋白基因座内经历发育程序性DNA双链断裂(DSB)的能力是独特的,以便在称为类别转换重组(CSR)的过程中产生功能性抗体。因此,转换B细胞提供了一个很好的模型来研究细胞对生理DSB的反应。经历CSR的B细胞触发DNA损伤反应(DDR)途径,其向细胞发出信号以暂停并修复DNA断裂,或者如果不能解决损伤则经历凋亡。DDR途径是对DNA损伤的初始细胞反应,其在肿瘤发生的早期被激活,但在癌症进展期间经常丢失。CSR期间DDR途径的破坏导致B细胞中免疫球蛋白转换受损和涉及IgH基因座的染色体易位。共济失调-毛细血管扩张症突变基因(ATM)是感受和响应DNA损伤的关键协调者。ATM缺陷的B细胞具有受损的CSR并且经常产生涉及免疫球蛋白重链基因座的染色体易位。在这方面,ATM的改变已被检测到在许多淋巴恶性肿瘤。ATM在维持B谱系细胞基因组稳定性中的确切作用仍然未知。在这个建议中,我们寻求开发的方法来研究机制,规范ATM招聘程序的DNA断裂在B细胞进行类转换。DSB修复复合物的定位和分子评估将阐明CSR期间DDR的组成部分。此外,我们将检查参与主动免疫应答的B细胞的限定群体,以确定ATM和DDR的其他成员被募集到IgH基因座的特定群体。在我们的第二个目标中,我们将进一步测试促进ATM募集到IgH位点的确切DNA序列。综上所述,这些研究将进一步确定在ATM缺陷型B细胞中调节基因组稳定性维持的机制,为治疗靶点的开发提供见解。公共卫生相关性:B细胞淋巴瘤是共济失调-毛细血管扩张症患者死亡的主要原因。本提案中的研究旨在了解促进B细胞致癌事件的基本机制,这也适用于AT患者中发生的其他癌症。这些发现可能导致AT患者癌症的新的和合理的治疗靶点的发展。
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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{{ truncateString('JOHN P MANIS', 18)}}的其他基金
Normalization of Sickle Cell Disease bone marrow niche defects by RBC transfusion
通过红细胞输注使镰状细胞病骨髓生态位缺陷正常化
- 批准号:
10494383 - 财政年份:2022
- 资助金额:
$ 18.62万 - 项目类别:
Normalization of Sickle Cell Disease bone marrow niche defects by RBC transfusion
通过红细胞输注使镰状细胞病骨髓生态位缺陷正常化
- 批准号:
10682593 - 财政年份:2022
- 资助金额:
$ 18.62万 - 项目类别:
Immune repertoire and function in typical and atypical SCID
典型和非典型 SCID 的免疫组库和功能
- 批准号:
9027475 - 财政年份:2012
- 资助金额:
$ 18.62万 - 项目类别: