TempO-Seq for Preserved Tissues in Toxicity Testing Phase II
毒性测试第二阶段中保存组织的 TempO-Seq
基本信息
- 批准号:9202942
- 负责人:
- 金额:$ 97.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-18 至 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAflatoxinsAnimal ModelAnimal TestingAnimalsArchivesAreaBioinformaticsBiological AssayBiological MarkersBiological PreservationBreast Cancer PatientCellsClinicalComputer SimulationConfidential InformationDataDatabasesDetectionDevelopmentDiagnosisDietDiseaseDoseFormalinFreezingFrozen SectionsGene ExpressionGene Expression ProfilingGenesGenetic TranscriptionHealthHistologyHumanIn VitroInvestmentsKidneyLigationLiteratureLiverLungMalignant neoplasm of prostateMeasurementMeasuresMethodsMolecular ProfilingNational Institute of Environmental Health SciencesOligonucleotidesOutcomeParaffin EmbeddingParaffin TissuePathway interactionsPatientsPerformancePharmaceutical PreparationsPhasePhenotypePrognostic MarkerProstateRNARattusReproducibilitySafetySamplingSourceStudy SectionTestingTherapeuticTimeTissue EmbeddingTissue MicroarrayTissuesToxic effectToxicity TestsToxicologyTranslational ResearchValidationbasecancer biomarkerscancer subtypescostdesigndetectordiagnostic biomarkerdifferential expressionimprovedin vitro Assayin vitro Modelin vivoinnovationinterestmalignant breast neoplasmmolecular phenotypephenotypic biomarkerprognosticprogramsresponsesafety testingsuccesstargeted sequencingtherapeutic targettranscriptometranscriptome sequencingtranslational diagnosticstranslational study
项目摘要
PROJECT SUMMARY
We have met or exceeded the Phase I success criteria; developed the capture free ligation-based TempO-
Seq gene expression assay; implemented, validated, and offered early access to the NIEHS TempO-Seq
rat surrogate assay for profiling RNA, cell lysates, and lysates of formalin fixed, paraffin embedded (FFPE)
tissue as small as 0.01mm3; and shown that the NIEHS human S1500+ TempO-Seq assay measures
differential expression that is highly correlated to RNAseq and identified prostate cancer biomarkers and
therapeutic targets from archived prostate FFPE. This Phase II program will address an NIEHS area of
special interest Topic (A.) “Development and validation of alternative test methods to protect human and
animal health while reducing, refining, or replacing animal tests”. We will validate the use of the rat whole
transcriptome assay and a human whole transcriptome assay in which the NIEHS S1500 rate surrogate is
embedded for profiling archived rat and clinical FFPE samples. We will confirm that the surrogate assay
data can be used in silico to accurately predict gene expression changes across the whole transcriptome,
though only a few thousand genes are directly measured. We will demonstrate that the TempO-Seq whole
transcriptome assays can profile many more samples than RNAseq for the same cost, and that the
surrogate assay lowers cost even further. Consequently, the TempO-Seq assay of FFPE will permit the
archives of animal FFPE to be mined cost effectively, providing in vivo molecular phenotypes for
compounds tested in the past, without having to repeat animal studies. We will demonstrate this by profiling
archived FFPE provided by NIEHS from several toxicity and dietary studies for which there is associated
RNAseq, microarray, and/or histology to correlate with TempO-Seq results. We showed in Phase I that the
precision of the TempO-Seq assay provides “between animal” average CVs of <10%, and that this
precision enables identification of molecular signatures for differential ED50s. This will improve the ability of
medicinal chemists to increase the therapeutic safety window of drugs, and will be useful for validating in
vitro assays for use in order to spare animal studies. It will also enable toxicity to be detected at lower doses
and earlier time points, thus permitting the size of animal studies to be reduced or discontinuing compounds
early before investment in long term animal models, significantly reducing clinical safety testing. By dosing
rats with reference compounds and correlating histology to TempO-Seq data, we will demonstrate that
precise ED50s for genes and pathway signatures can be established. Clinical utility will be demonstrated
from a translational study of archived FFPE from breast cancer patients for which 5-, 10-, 20-year outcomes
are known, and from which molecular phenotypes of breast cancer subtypes and prognostic biomarkers will
be identified, confirming and extending what is known today.
项目摘要
我们已经达到或超过了第一阶段的成功标准;开发了基于捕获自由连接的克里思-
Seq基因表达检测;实施、验证并提供NIEHS TempO-Seq的抢先体验
用于分析RNA、细胞裂解物和福尔马林固定、石蜡包埋(FFPE)裂解物的大鼠替代试验
组织小至0.01mm3;并显示NIEHS人S1500+ TempO-Seq测定测量了
与RNAseq高度相关的差异表达和鉴定的前列腺癌生物标志物,
来自存档前列腺FFPE的治疗靶点。该第二阶段计划将解决NIEHS领域,
特殊兴趣主题(A.)“开发和验证替代测试方法,以保护人类和
动物健康,同时减少,改进或取代动物试验”。我们将验证大鼠整体的使用
转录组测定和人全转录组测定,其中NIEHS S1500速率替代物是
用于分析存档的大鼠和临床FFPE样本。我们将确认替代试验
数据可以在计算机中用于准确预测整个转录组中的基因表达变化,
尽管只有几千个基因被直接测量。我们将证明TempO-Seq整体
转录组测定可以以相同的成本分析比RNAseq更多的样品,
替代测定甚至进一步降低了成本。因此,FFPE的TempO-Seq测定法将允许对FFPE进行测序。
动物FFPE档案被有效地挖掘,提供体内分子表型,
过去测试的化合物,而不必重复动物研究。我们将通过分析
NIEHS提供的存档FFPE来自几项毒性和饮食研究,
RNaseq、微阵列和/或组织学与TempO-Seq结果相关。我们在第一阶段表明,
TempO-Seq测定的精确度提供了<10%的“动物间”平均CV,并且这一点是重要的。
精密度使得能够鉴定差异ED 50的分子特征。这将提高
药物化学家,以增加药物的治疗安全窗口,并将有助于验证在
使用体外试验,以避免动物研究。它还将使毒性能够在较低剂量下检测到
和更早的时间点,从而允许减少动物研究的规模或停止化合物
在投资长期动物模型之前,这大大减少了临床安全性测试。按给药
大鼠与参考化合物和相关的组织学TempO-Seq数据,我们将证明,
可以建立基因和途径标记的精确ED 50。将证明临床效用
来自一项对乳腺癌患者存档FFPE的转化研究,其5年、10年、20年结局
是已知的,并且从其中乳腺癌亚型的分子表型和预后生物标志物将
确认和扩展今天所知道的。
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('BRUCE E. SELIGMANN', 18)}}的其他基金
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Functional Read-Out Enabling High Compound Throughput Toxicokinetic Assays
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TempO-Seq Profiling of RNA Epitranscriptomic Modifications
RNA 表观转录组修饰的 TempO-Seq 分析
- 批准号:
9890040 - 财政年份:2018
- 资助金额:
$ 97.99万 - 项目类别:
TempO-Seq Profiling of RNA Epitranscriptomic Modifications
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- 批准号:
10220107 - 财政年份:2018
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$ 97.99万 - 项目类别:
TempO-Seq Gene Expression Profiling of Intracellular Stained FACS Sorted Cells
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单细胞 II 期多重 mRNA 和 miRNA 分析
- 批准号:
9356539 - 财政年份:2014
- 资助金额:
$ 97.99万 - 项目类别:
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