Basic Research for Diagnostics and Surveillance in Lower Resource Environments
低资源环境诊断和监测基础研究
基本信息
- 批准号:10468606
- 负责人:
- 金额:$ 74.17万
- 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:2021-08-12 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVAnimalsBasic ScienceBiological AssayBusinessesCOVID detectionCenters for Disease Control and Prevention (U.S.)Cessation of lifeChemistryClinicalCommunitiesComputer softwareDNADataDemographyDiagnosticDiagnostic Reagent KitsDiagnostics ResearchDiseaseDropsEmergency SituationEnzymatic BiochemistryEnzymesEpidemicFailureFoundationsFutureGuidelinesHumanInformation SystemsKnowledgeLearningMalaiseManufacturer NameMedicareMissionMolecular DiagnosisMolecular EvolutionNational Institute of Allergy and Infectious DiseaseNucleic AcidsOralPaperPathogen detectionPatientsPhysiciansProblem SolvingProcessRNARegulationReproducibilityResearchResearch PersonnelResistanceResource-limited settingResourcesSamplingScienceShipsSpecific qualifier valueSpeedSymptomsSystemTemperatureTestingThermodynamicsTimeTravelVaginaWritingbasecare costscostdeep sequencingdesigneconomic impactemerging pathogenexperimental studyflexibilitygenetic informationinnovationmeetingsmeltingmolecular recognitionnew technologypandemic diseasepathogenpreventrectalrelative costresponsestatistics
项目摘要
Basic Research to Diagnostics and Surveillance in Lower Resource Environments
Foundation for Applied Molecular Evolution
Steven A. Benner
ABSTRACT
We will deliver to the NIAID and CDC communities, through basic research, a scientific understanding of
pairing, mispairing, and enzymology of natural DNA and RNA (collectively xNA) that goes deeper than the
axiom that "A pairs with T, and G pairs with C". The experiments are designed to learn:
(a) Why robust multiplexed PCR (mPCR) for clinical use seems impossible with more than 20-30 targets.
(b) Why conventional expedients (including careful primer and probe design, internal nesting, and external
tagging) fail to robustly support multiplexing beyond ~30 targets.
(c) Why those failures are not reproducible from sample to sample.
(d) Why conventional multiplexes targeting n targets often collapse when an n+1th target is added. This
prevents, when a new pathogen emerges (as for 2019-nCoV), a diagnostics maker from simply adding a new
target to an existing mPCR kit, thereby meeting the emergency need.
(e) Why manufacturing specs become increasingly more demanding as the level of multiplexing increases.
These problems restrain 21st century diagnostics to two 20th century design and regulatory paradigms.
(i) A "guess-then-test" paradigm for singleplexed molecular diagnosis, which requires physician to guess
which pathogen might be associated with patient malaise, prescribe a ~$150 singleplexed test based on that
guess, and re-prescribe further tests until a guess proves correct.
(ii) The "inflexible-multiplexed-panel" paradigm. Here, assays are bundled into a multiplex appropriate for a
specific sample and symptom set; failure (d) prevents that multiplex from changing for emerging diseases.
By developing the science of both natural and unnatural DNA (including artificially expanded genetic
information systems, AEGIS, and self avoiding molecular recognition systems, SAMRS), this project will deliver
to researchers, manufacturers, and the FDA science to meet the 21st century NIAID mission. We will:
Task 1. Complete thermodynamic and enzyme rules to place SAMRS optimally in primers that target both DNA
and RNA. Rules will be metricked by comparing predictions made with these rules to experiments.
Task 2. Metric, by deep sequencing, mPCR failures (a) through (e).
Task 3. Metric how AEGIS and SAMRS mitigate or eliminate failures (a) through (e).
Task 4. Identify failure modes that arise with RNA targets specifically. Since RNA has folding options not
available to DNA, these modes may be especially resistant to nucleic acid innovations.
Task 5. Build a body of statistical knowledge for AEGIS-SAMRS mPCR, especially with respect to "add-ons",
quantitative amplification, and manufacturing tolerances. This will help move away from "guess-then-
test" and "inflexible-multiplexed-panel" paradigms, lowing cost, supporting FDA regulatory processes,
and better managing pandemics.
1
低资源环境诊断与监测基础研究
应用分子进化基金会
Steven A. Benner
摘要
我们将通过基础研究,向NIAID和CDC社区提供对以下问题的科学理解:
自然DNA和RNA(统称为xNA)的配对,错配和酶学,
公理“A与T配对,G与C配对”。这些实验旨在学习:
(a)为什么临床使用的稳健多重PCR(mPCR)似乎不可能超过20-30个靶点。
(b)为什么传统的实验(包括仔细的引物和探针设计,内部嵌套和外部嵌套)
标记)不能稳健地支持超过~30个靶的多路复用。
(c)为什么这些失败在不同的样品之间是不可重现的。
(d)为什么针对n个目标的传统多路复用经常在添加第n+1个目标时崩溃。这
当一种新的病原体出现时(如2019-nCoV),诊断制造商可以简单地添加一种新的
针对现有的mPCR试剂盒,从而满足紧急需求。
(e)为什么随着多路复用水平的提高,制造规格变得越来越苛刻。
这些问题限制了21世纪的诊断两个20世纪的设计和监管范式。
(i)一个“猜测然后测试”的单分子诊断范例,需要医生猜测
哪种病原体可能与患者不适有关,基于此开一个150美元的单重测试
猜测,并重新规定进一步的测试,直到猜测证明正确。
(ii)“多重-多重-面板”范例。在这里,测定被捆绑到适合于分析的多路复用中。
特定样本和症状组;失败(d)防止多重性因新出现疾病而改变。
通过发展自然和非自然DNA科学(包括人工扩增的基因),
信息系统,AEGIS和自我回避分子识别系统,SAMRS),该项目将提供
为研究人员、制造商和FDA科学提供支持,以满足21世纪世纪NIAID的使命。我们将:
任务1.完整的热力学和酶规则,将SAMRS最佳地放置在靶向两种DNA的引物中
和RNA。规则将通过将这些规则的预测与实验进行比较来衡量。
任务2.通过深度测序度量mPCR失败(a)至(e)。
任务3.衡量AEGIS和SAMRS如何减轻或消除故障(a)至(e)。
任务4.识别特定RNA靶点出现的故障模式。由于RNA具有折叠选择,
这些模式可能特别抵抗核酸创新。
任务5.建立AEGIS-SAMRS mPCR的统计学知识体系,特别是关于“附加”,
定量放大和制造公差。这将有助于摆脱“猜测,然后-
“测试”和“多路复用面板”模式,降低成本,支持FDA监管流程,
更好地控制流行病。
1
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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STEVEN A BENNER其他文献
STEVEN A BENNER的其他文献
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{{ truncateString('STEVEN A BENNER', 18)}}的其他基金
Basic Research for Diagnostics and Surveillance in Lower Resource Environments
低资源环境诊断和监测基础研究
- 批准号:
10669039 - 财政年份:2021
- 资助金额:
$ 74.17万 - 项目类别:
Easily Used Kits to Evolve Reagents that Covalently Tag and Inactivate Proteins
易于使用的试剂盒可进化出共价标记和灭活蛋白质的试剂
- 批准号:
10626917 - 财政年份:2021
- 资助金额:
$ 74.17万 - 项目类别:
Easily Used Kits to Evolve Reagents that Covalently Tag and Inactivate Proteins
易于使用的试剂盒可进化出共价标记和灭活蛋白质的试剂
- 批准号:
10478279 - 财政年份:2021
- 资助金额:
$ 74.17万 - 项目类别:
Easily Used Kits to Evolve Reagents that Covalently Tag and Inactivate Proteins
易于使用的试剂盒可进化出共价标记和灭活蛋白质的试剂
- 批准号:
10298982 - 财政年份:2021
- 资助金额:
$ 74.17万 - 项目类别:
Equipment Supplement to 1R01GM141391-01A1 (Easily Used Kits to Evolve Reagents that Covalently Tag and Inactivate Proteins)
1R01GM141391-01A1 的设备补充(易于使用的试剂盒,用于进化共价标记和灭活蛋白质的试剂)
- 批准号:
10580301 - 财政年份:2021
- 资助金额:
$ 74.17万 - 项目类别:
PHS2019-02 Omnibus Solic of the NIH, CDC, and FDA for SBIR Apps No Clinical Trial (Parent SBIR R43/4
PHS2019-02 NIH、CDC 和 FDA 的 SBIR 应用程序综合 Solic 尚未进行临床试验(母公司 SBIR R43/4
- 批准号:
10476977 - 财政年份:2021
- 资助金额:
$ 74.17万 - 项目类别:
Reagents to Chemically Tag Specific Coronavirus Spike Proteins
化学标记特定冠状病毒刺突蛋白的试剂
- 批准号:
10259048 - 财政年份:2021
- 资助金额:
$ 74.17万 - 项目类别:
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