High Throughput Screens of Novel Radiation Sensitizers and Protectors
新型辐射敏化剂和保护剂的高通量筛选
基本信息
- 批准号:8134255
- 负责人:
- 金额:$ 28.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-09-05 至 2013-07-31
- 项目状态:已结题
- 来源:
- 关键词:AccidentsAllelesBaltimoreBiochemical PathwayBiological AssayCell LineCell SurvivalCellsChromosomal InstabilityClinicClinicalDevicesDoseEmergency SituationEventExposure toFDA approvedFluorescenceGenesGenomic InstabilityGoalsHealthHumanIndividualIonizing radiationLeadLibrariesMalignant NeoplasmsMarylandMeasuresMicronucleus TestsMilitary PersonnelMolecular TargetMutationNormal tissue morphologyNuclearPathway interactionsPatientsPharmaceutical PreparationsPreclinical Drug EvaluationProteinsRadiationRadiation OncologyRadiation therapyRadiation-Protective AgentsRadiation-Sensitizing AgentsRadioRadioactiveRadiobiologyReporterResearchRoboticsTechnologyTerrorismTestingTimeUniversitiesbasecancer cellcell killingcell typeclinically relevantdirty bombdrug discoveryemergency service responderhigh throughput screeningimprovedinterestirradiationkillingsneoplastic cellnovelnovel therapeuticsradiation effecttumor
项目摘要
DESCRIPTION (provided by applicant): This is a new application that brings together expertise in radiation biology and robotic high throughput drug screen technology to identify new radiation sensitizers and protectors for use in clinical radiation oncology and in the event of radiological terrorism. Three specific aims are proposed. Specific Aim 1 will implement a high throughput cell-based screen to identify compounds that can sensitize/protect human cells to/from ionizing radiation. This is a drug discovery aim that will allow us to identify lead molecules that are radio-sensitizers or radio-protectors from a library consisting of ~40,000 compounds. Specific Aim 2 will validate the results obtained in Aim 1 using clonogenic cell survival assays. Different drug concentrations and exposure times will be investigated at increasing radiation doses. Aim 2 will also test the hypothesis that radiation protectors are effective when used after irradiation. Once we have confirmed the initial observations regarding sensitization or protection, we will use isogenic cells that lack one or both alleles of genes known to be disrupted in tumor cells to determine whether lead compounds sensitize/protect differentially in wild type cells versus cells with well characterized mutations commonly found in cancer. Specifically we will test the hypothesis that compounds will differentially sensitize/protect wild type cells compared with cells containing genetic alterations commonly found in cancer cells. Specific Aim 3 will test the hypothesis that the sensitizers/protectors identified in Aim 1 and confirmed in Aim 2 will not predispose surviving cells to enhanced genomic instability. Exposure to clinically relevant doses of radiation in the presence of sensitizers or protectors will not kill all cells. Using a green fluorescence protein-based reporter assay we will test the hypothesis that the progeny of cells surviving irradiation +/-sensitizer or protector are not more likely to manifest genomic instability as measured by delayed mutation and hyperrecombination. Using a micronucleus assay we will test the hypothesis that the progeny cells surviving irradiation +/- sensitizer or protector are not more likely to manifest genomic instability as measured by delayed chromosomal instability. All technology and cell lines are available and in place at the University of Maryland. We have the expertise to identify new radiation sensitizers/protectors for use in the clinic and in the event of radiological terrorism. Successfully achieving the proposed research goals will be a significant contribution to patients undergoing radiation therapy and to the public in the event of terrorism involving radioactive material. PUBLIC HEALTH RELEVENCE: There are two feasible and potentially very significant goals to this application. The first is to use state of the art technologies to identify compounds that can sensitize cancer cells to radiation- induced cell killing and thus improve radiation therapy. The second is to use those same technologies to find unique compounds that can protect against deleterious radiation effects and thus protect individuals in the event of a radiological incident.
描述(由申请人提供):这是一项新应用,汇集了放射生物学和机器人高通量药物筛选技术的专业知识,以确定用于临床放射肿瘤学和放射恐怖主义事件的新放射增敏剂和保护剂。提出了三个具体目标。具体目标 1 将实施基于细胞的高通量筛选,以识别能够使人体细胞对电离辐射敏感/保护人体细胞免受电离辐射影响的化合物。这是一个药物发现目标,使我们能够从由约 40,000 种化合物组成的库中识别出放射增敏剂或放射防护剂的先导分子。具体目标 2 将使用克隆细胞存活测定验证目标 1 中获得的结果。将在增加辐射剂量的情况下研究不同的药物浓度和暴露时间。目标 2 还将检验辐射防护剂在辐射后使用时是否有效的假设。一旦我们确认了有关致敏或保护的初步观察结果,我们将使用缺乏已知在肿瘤细胞中被破坏的基因的一个或两个等位基因的同基因细胞来确定先导化合物在野生型细胞中与具有癌症中常见突变的细胞中是否有差异的致敏/保护作用。具体来说,我们将测试以下假设:与癌细胞中常见的含有遗传改变的细胞相比,化合物会对野生型细胞产生不同的敏化/保护。具体目标 3 将检验以下假设:目标 1 中确定并在目标 2 中确认的敏化剂/保护剂不会使存活细胞倾向于增强基因组不稳定性。在存在敏化剂或保护剂的情况下暴露于临床相关剂量的辐射不会杀死所有细胞。使用基于绿色荧光蛋白的报告基因检测,我们将测试以下假设:在辐射+/-敏化剂或保护剂中幸存的细胞后代不太可能表现出基因组不稳定性(通过延迟突变和超重组测量)。使用微核测定,我们将测试以下假设:在辐射+/-敏化剂或保护剂中幸存的子代细胞并不更有可能表现出基因组不稳定性(通过延迟染色体不稳定性来测量)。所有技术和细胞系均在马里兰大学可用并到位。我们拥有专业知识,可以识别用于诊所和放射性恐怖主义事件的新型辐射敏化剂/防护剂。成功实现拟议的研究目标将为接受放射治疗的患者以及涉及放射性物质的恐怖主义事件中的公众做出重大贡献。公共卫生相关性:此应用程序有两个可行且可能非常重要的目标。第一个是使用最先进的技术来鉴定可以使癌细胞对辐射诱导的细胞杀伤敏感的化合物,从而改善放射治疗。第二个是使用相同的技术来寻找独特的化合物,可以防止有害的辐射影响,从而在发生放射性事件时保护个人。
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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William F Morgan其他文献
William F Morgan的其他文献
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{{ truncateString('William F Morgan', 18)}}的其他基金
2010 Radiation Oncology Gordon Research Conference
2010年放射肿瘤学戈登研究会议
- 批准号:
7800639 - 财政年份:2010
- 资助金额:
$ 28.99万 - 项目类别:
High Throughput Screens of Novel Radiation Sensitizers and Protectors
新型辐射敏化剂和保护剂的高通量筛选
- 批准号:
7459311 - 财政年份:2008
- 资助金额:
$ 28.99万 - 项目类别:
High Throughput Screens of Novel Radiation Sensitizers and Protectors
新型辐射敏化剂和保护剂的高通量筛选
- 批准号:
7683249 - 财政年份:2008
- 资助金额:
$ 28.99万 - 项目类别:
High Throughput Screens of Novel Radiation Sensitizers and Protectors
新型辐射敏化剂和保护剂的高通量筛选
- 批准号:
7911884 - 财政年份:2008
- 资助金额:
$ 28.99万 - 项目类别:
BYSTANDER EFFECTS AND X RAY INDUCED GENOMIC INSTABILITY
旁观者效应和 X 射线引起的基因组不稳定性
- 批准号:
6260258 - 财政年份:2001
- 资助金额:
$ 28.99万 - 项目类别:
BYSTANDER EFFECTS AND X RAY INDUCED GENOMIC INSTABILITY
旁观者效应和 X 射线引起的基因组不稳定性
- 批准号:
6697036 - 财政年份:2001
- 资助金额:
$ 28.99万 - 项目类别:
BYSTANDER EFFECTS AND X RAY INDUCED GENOMIC INSTABILITY
旁观者效应和 X 射线引起的基因组不稳定性
- 批准号:
6497943 - 财政年份:2001
- 资助金额:
$ 28.99万 - 项目类别:
BYSTANDER EFFECTS AND X RAY INDUCED GENOMIC INSTABILITY
旁观者效应和 X 射线引起的基因组不稳定性
- 批准号:
6628427 - 财政年份:2001
- 资助金额:
$ 28.99万 - 项目类别:
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