Protein kinase C-delta regulates chromatin remodeling and DNA repair
蛋白激酶 C-delta 调节染色质重塑和 DNA 修复
基本信息
- 批准号:10393176
- 负责人:
- 金额:$ 0.25万
- 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:2021-04-21 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:ABL1 geneAddressAffectApoptosisApoptoticBindingBiological AssayCancer BiologyCell NucleusChromatinChromatin StructureChronicComet AssayDNADNA DamageDNA RepairDNA Repair PathwayDataDevelopmentDiagnosisDouble Strand Break RepairEnzymesExposure toFellowshipGoalsHead and Neck CancerHistone DeacetylaseHistonesImmunoprecipitationIn VitroLeadMalignant NeoplasmsMass Spectrum AnalysisMediatingMethodsModificationMolecularMolecular ConformationNonhomologous DNA End JoiningNormal tissue morphologyNuclearNuclear ImportNuclear ProteinOperative Surgical ProceduresOral cavityOral mucous membrane structurePathway interactionsPatientsPhosphorylationPhosphotransferasesPlayProductionProtein InhibitionProtein Tyrosine KinaseProteinsQuality of lifeRadiation ProtectionRegulationRepair ComplexReporterResearchResearch PersonnelResearch TrainingRoleSRC geneSalivaSalivary GlandsSiteTherapeutic InterventionTrainingTyrosine Kinase InhibitorXerostomiaalpha Karyopherinscancer cellchemotherapychromatin remodelingexperienceexperimental studyhead and neck cancer patienthistone acetyltransferasehistone modificationhomologous recombinationin vivoinhibitor/antagonistirradiationnoveloral biologyoral infectionoral tissueprotein activationprotein complexprotein functionprotein kinase C-deltarepairedresponsesalivary acinar cellside effectskillssmall hairpin RNA
项目摘要
PROJECT ABSTRACT
Head and neck cancer (HNC) accounts for 4% of all cancers in the US, and HNC patients are mostly treated
with irradiation (IR) therapy or combination of treatments. Unfortunately, besides killing cancer cells, IR treatment
also kills non-tumor cells in the oral cavity and damages the salivary glands, causing side effects such as chronic
oral infection, decreased saliva production, and xerostomia. IR-induced damage to the salivary glands is thought
to occur in part due from loss of salivary acinar cells through apoptosis. Our lab has identified protein kinase C
delta (PKCδ) as a key regulator of IR-induced apoptosis in the salivary acinar cells in vitro and in the salivary
gland in vivo. We have shown that upon IR damage PKCδ is activated and imported into the nucleus. Although
we know that nuclear import of PKCδ is necessary for apoptosis, the mechanism of how nuclear PKCδ regulates
DNA damage-induced apoptosis is unknown. Previous studies from our lab have suggested that PKCδ does not
activate the apoptotic pathway directly but may instead regulate upstream pathways that contribute to the DNA
damage response and DNA repair. My preliminary studies suggest a novel mechanism of PKCδ-mediated
regulation of apoptosis through chromatin remodeling and DNA repair. My preliminary data shows that depletion
of PKCδ increases IR-induced DNA damage repair, and that PKCδ regulates DNA repair through both non-
homologous end joining (NHEJ) and homologous recombination (HR) pathways. Furthermore, my preliminary
data suggests that PKCδ may regulate chromatin structure through altering histone modifications. Thus, my
overall goal is to understand mechanistically how nuclear PKCδ regulates chromatin accessibility and
DNA repair in response to IR damage. In Aim 1 I will characterize the role of nuclear PKCδ in NHEJ and HR
pathways and analyze whether PKCδ is biased toward NHEJ or HR using in vivo fluorescent reporter assay. I
will also determine if PKCδ affects the formation of NHEJ and HR repair complexes at sites of double-stranded
breaks (DSBs) and perform rapid immunoprecipitation mass spectrometry to identify chromatin interacting
proteins influenced by PKCδ. In Aim 2 I will ask how PKCδ regulates histone modifications and chromatin
structure, and how this relates to DNA repair regulation. I will explore the role of PKCδ in histone modifications
before and after IR, and the nuclear function of PKCδ in chromatin remodeling. To further understand the
mechanism of this regulation, we will analyze if PKCδ regulates upstream histone-modifying enzymes. Overall,
my proposed studies should enhance our understanding of the mechanism by which PKCδ regulates DNA
damage-induced apoptosis, and may lead to new safe therapeutic interventions to protect salivary gland and
oral tissues of patients undergoing IR for HNC. This F32 fellowship will also provide me with specific scientific
and research training, including the development of new research skills, and exposure to basic and translational
cancer and oral biology. Together with a wide variety of professional development opportunities, this training will
prepare me for my long-term goal to become an independent cancer researcher.
项目摘要
头颈癌(HNC)占美国所有癌症的4%,HNC患者大多接受治疗
用辐射(IR)疗法或治疗的组合。不幸的是,除了杀死癌细胞,红外治疗
也会杀死口腔中的非肿瘤细胞,损害唾液腺,引起慢性副作用,
口腔感染、唾液分泌减少和口腔干燥。据认为,红外线引起的唾液腺损伤
部分原因是由于唾液腺泡细胞通过凋亡而丧失。我们的实验室已经鉴定出蛋白激酶C
在体外和唾液腺中,PKC δ作为IR诱导的腺泡细胞凋亡的关键调节因子,
体内腺体。我们已经表明,在IR损伤时,PKC δ被激活并输入到细胞核中。虽然
我们知道PKC δ的核输入是细胞凋亡所必需的,核PKC δ如何调节细胞凋亡的机制是,
DNA损伤诱导的细胞凋亡是未知的。我们实验室以前的研究表明,PKC δ不
直接激活凋亡途径,但可能会调节上游途径,有助于DNA
损伤反应和DNA修复。我的初步研究表明,PKC δ介导的一种新的机制,
通过染色质重塑和DNA修复调节细胞凋亡。我的初步数据显示
PKC δ增加IR诱导的DNA损伤修复,并且PKC δ通过两种非-
同源末端连接(NHEJ)和同源重组(HR)途径。此外,初步
数据表明PKC δ可能通过改变组蛋白修饰来调节染色质结构。所以我的
总体目标是从机制上了解核PKC δ如何调节染色质可及性,
DNA修复反应IR损伤。目的1:研究PKC δ在NHEJ和HR中的作用
并使用体内荧光报告基因测定分析PKC δ是否偏向NHEJ或HR。我
还将确定PKC δ是否影响NHEJ和HR修复复合物在双链
断裂(DSB),并进行快速免疫沉淀质谱法,以确定染色质相互作用
PKC δ影响的蛋白质。在目标2中,我将探讨PKC δ如何调节组蛋白修饰和染色质
结构,以及这与DNA修复调节的关系。我将探讨PKC δ在组蛋白修饰中的作用
以及PKC δ在染色质重构中的核功能。进一步了解
为了阐明这种调节的机制,我们将分析PKC δ是否调节上游组蛋白修饰酶。总的来说,
我所提出的研究应该能增强我们对PKC δ调节DNA的机制的理解
损伤诱导的细胞凋亡,并可能导致新的安全的治疗干预,以保护唾液腺和
对HNC进行IR的患者的口腔组织。这个F32奖学金也将为我提供具体的科学
和研究培训,包括新的研究技能的发展,并接触基础和翻译
癌症和口腔生物学。加上各种各样的专业发展机会,这项培训将
为我成为一名独立的癌症研究人员的长期目标做好准备。
项目成果
期刊论文数量(0)
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{{ truncateString('Trisiani Affandi', 18)}}的其他基金
Protein kinase C-delta regulates chromatin remodeling and DNA repair - Supplement
蛋白激酶 C-delta 调节染色质重塑和 DNA 修复 - 补充
- 批准号:
10401150 - 财政年份:2021
- 资助金额:
$ 0.25万 - 项目类别:
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