A new diagnostic tool for rapid detection and characterization of REPEAT SEQUENCES in inherited diseases
一种新的诊断工具,用于快速检测和表征遗传性疾病中的重复序列
基本信息
- 批准号:10354657
- 负责人:
- 金额:$ 25.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-15 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAge of OnsetAtaxiaAtomic Force MicroscopyBar CodesBenchmarkingBioinformaticsCGG repeatCapillary ElectrophoresisChildClinicClinicalComplexCoupledDNADNA Sequence AlterationDecision MakingDetectionDevelopmentDiagnosisDiagnosticDiseaseDisease ManagementEarly DiagnosisElderlyEquilibriumFMR1FXTASFamilyFamily PlanningFamily memberFragile X SyndromeGenerationsGenesGeneticGenetic AnticipationGenetic CounselingGenetic PhenomenaGenetic RiskGenomeGenomic DNAGenomicsGoalsHealthcareHereditary DiseaseHospitalsIndividualInheritedInsurance CarriersLabelLeadLengthLesionMJD1 proteinMeasuresMedicalMedical GeneticsMeiosisMemory DisordersMethodologyMethodsMolecularMonitorMood DisordersMovementMutationNaturePatient MonitoringPatientsPerformancePersonsPhenotypePhysiciansPolymerasePolymerase Chain ReactionProceduresProcessProduct LabelingPrognosisRelative RisksRiskSamplingSeveritiesSkeletal MuscleSouthern BlottingSpeedSpinocerebellar AtaxiasStretchingSymptomsSystemTechniquesTechnologyTestingTimeTremorTrinucleotide Repeat ExpansionTrinucleotide RepeatsUnited StatesVariantWalkingbasebiobankclinically relevantcostdesigndiagnostic toolgenetic analysisgenetic disorder diagnosisgenetic testinghealth care economicsimprovedmembermultiplex assaymultiplex detectionmutantnanoparticlenanoporenervous system disordernew therapeutic targetnext generation sequencingnon-geneticnovel diagnosticsnovel strategiesoffspringpatient stratificationrapid detectionrisk stratificationscreeningsequencing platformsuccesstargeted treatmenttoolvirtual
项目摘要
=. PROJECT SUMMARY …...
Ataxia is a discoordination of voluntary muscle movement and can be seen as the primary symptom of multiple
disorders including genetic and non-genetic etiologies. Several genes are implicated in causing Spinocerebellar
ataxia through trinucleotide repeat expansions (TREs) and are thought to affect between 1.5 to 4 per 10,000
people globally. Similar trinucleotide repeat expansions in the FMR1 gene, including potentially symptomatic
premutations, can be found in around 1 in 300 people in the United States. Detection of repeat expansion
disorders in a family are important for understanding genetic risks and early detection in at risk members,
especially since unstable repeat expansions lead to the phenomenon of genetic anticipation, where symptoms
can present earlier or more severely across generations. Additionally, several recent studies have suggested
development of targeted therapies specifically targeting expanded repeats as a novel therapeutic target. As
such, earlier and rapid detection of these disorders is crucial for advancing their medical management.
Traditionally, short TRE targets are assessed via repeat-primed PCR (PR-PCR) and capillary
electrophoresis, while longer mutants are confirmed via Southern blotting. This is clinically important, especially
where repeat lengths outside of the range quantifiable by PR-PCR are diagnostically relevant. Testing for most
TRE genes remains difficult for short read sequencing platforms, where repeat tract lengths exceed average
read length (~100 bp for Illumina systems). Long-read sequencing technologies like PacBio and Oxford
Nanopore have shown success in measuring TREs, however a combination of high costs, large quantities of
DNA input, complex bioinformatics, problems determining repeat region boundaries, and high error rates makes
them an unlikely solution for widespread screening in their current state
We developed a solution, PRECYSE, based on high-speed atomic force microscopy (HSAFM) paired
with unique ‘nanoparticle barcoding’ that can potentially characterize complex structural variants for numerous
ataxia conditions simultaneously at much lower cost than possible with next generation sequencing (NGS)
sequencing and other emerging approaches. This extremely sensitive technique can be conducted without using
polymerase chain reaction (PCR) and can span a very wide range of possible target sizes, thereby allowing
extension to virtually unlimited molecular lengths. Our hypothesis is that this technology can be easily adapted
to multiplexed detection of TRE targets of practically any length. If successfully developed, our new approach
will change the way clinicians identify, understand, and monitor changes in the genome caused by trinucleotide
repeat expansion diseases through multiplexed panels. At the end of this R21 project, we will have a platform
for multiplexed genomic analysis that successfully purifies and detects trinucleotide repeat targets. However, a
follow-on larger scale (50-60 samples) planned R01 project will provide statistical significance and further refine
the methodology.
=.项目概要......
共济失调是一种随意肌肉运动的不协调,可以被视为多发性硬化症的主要症状。
包括遗传和非遗传病因的疾病。有几个基因与脊髓小脑症有关
通过三核苷酸重复扩增(TREs)导致共济失调,据认为影响1.5至4/10,000
全球的人。FMR 1基因中类似的三核苷酸重复扩增,包括潜在的症状性
在美国,大约每300人中就有1人有这种突变。重复扩增检测
家族中的疾病对于了解遗传风险和早期发现处于风险中的成员是重要的,
特别是因为不稳定的重复扩增导致遗传预期的现象,其中症状
可以在几代人中更早或更严重地出现。此外,最近的几项研究表明,
开发特异性靶向扩展重复序列作为新的治疗靶点的靶向治疗。作为
这种早期和快速检测这些疾病对于促进其医疗管理至关重要。
传统上,通过重复引物PCR(PR-PCR)和毛细管PCR(PCR)来评估短TRE靶标。
电泳,而更长的突变体通过Southern印迹确认。这在临床上很重要,尤其是
其中在可通过PR-PCR定量的范围之外的重复长度是诊断相关的。测试大多数
TRE基因仍然难以用于短读段测序平台,其中重复序列长度超过平均值
读取长度(对于Illumina系统为~100 bp)。PacBio和Oxford等长读段测序技术
纳米孔已经在测量TREs方面显示出成功,然而,高成本、大量的纳米孔和纳米孔的组合是不可能的。
DNA输入,复杂的生物信息学,确定重复区域边界的问题,以及高错误率,
在他们目前的状态下,他们不太可能成为广泛筛查的解决方案。
我们开发了一种基于高速原子力显微镜(HSAFM)配对的解决方案PRECYSE。
具有独特的“纳米颗粒条形码”,可以潜在地表征许多
以比下一代测序(NGS)低得多的成本同时治疗共济失调
排序和其他新兴方法。这种极其敏感的技术可以在不使用
聚合酶链式反应(PCR)可以是一种非常有效的方法,并且可以跨越非常宽范围的可能的靶大小,从而允许
延伸到几乎无限的分子长度。我们的假设是这项技术可以很容易地适应
涉及实际上任何长度的TRE靶的多重检测。如果研发成功,我们的新方法
将改变临床医生识别、理解和监测三核苷酸引起的基因组变化的方式。
重复扩增疾病。在这个R21项目结束时,我们将有一个平台,
用于成功纯化和检测三核苷酸重复目标的多重基因组分析。但
后续更大规模(50-60份样本)计划的R 01项目将提供统计学意义并进一步完善
方法论。
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)
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Jason C Reed其他文献
Jason C Reed的其他文献
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{{ truncateString('Jason C Reed', 18)}}的其他基金
A new diagnostic tool for rapid detection and characterization of REPEAT SEQUENCES in inherited diseases
一种新的诊断工具,用于快速检测和表征遗传性疾病中的重复序列
- 批准号:
10682387 - 财政年份:2022
- 资助金额:
$ 25.57万 - 项目类别:
(PQD5) Mass Profiling Melanoma Responses to Improve Therapy Choices and Prognosis
(PQD5) 大规模分析黑色素瘤反应以改善治疗选择和预后
- 批准号:
8687449 - 财政年份:2014
- 资助金额:
$ 25.57万 - 项目类别:
(PQD5) Mass Profiling Melanoma Responses to Improve Therapy Choices and Prognosis
(PQD5) 大规模分析黑色素瘤反应以改善治疗选择和预后
- 批准号:
9067822 - 财政年份:2014
- 资助金额:
$ 25.57万 - 项目类别:
(PQD5) Mass Profiling Melanoma Responses to Improve Therapy Choices and Prognosis
(PQD5) 大规模分析黑色素瘤反应以改善治疗选择和预后
- 批准号:
8851546 - 财政年份:2014
- 资助金额:
$ 25.57万 - 项目类别:
Nanotechnologies for Determining Gene Expression Patterns from Single Cells
用于确定单细胞基因表达模式的纳米技术
- 批准号:
8657227 - 财政年份:2010
- 资助金额:
$ 25.57万 - 项目类别:
Nanotechnologies for Determining Gene Expression Patterns from Single Cells
用于确定单细胞基因表达模式的纳米技术
- 批准号:
8539804 - 财政年份:2010
- 资助金额:
$ 25.57万 - 项目类别:
Nanotechnologies for Determining Gene Expression Patterns from Single Cells
用于确定单细胞基因表达模式的纳米技术
- 批准号:
8146147 - 财政年份:2010
- 资助金额:
$ 25.57万 - 项目类别:
Nanotechnologies for Determining Gene Expression Patterns from Single Cells
用于确定单细胞基因表达模式的纳米技术
- 批准号:
7948880 - 财政年份:2010
- 资助金额:
$ 25.57万 - 项目类别:
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