Altered reverse transcriptase-dependent gene diversification mechanisms in Alzheimer's disease brains
阿尔茨海默病大脑中逆转录酶依赖性基因多样化机制的改变
基本信息
- 批准号:10758986
- 负责人:
- 金额:$ 8.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease therapeuticAlzheimer&aposs disease therapyAmyloid beta-Protein PrecursorAnimal ExperimentsAnimal ModelAutopsyBackBiological ModelsBrainBrain regionCell modelComplementary DNACopy Number PolymorphismDNADNA strand breakDataDiseaseDown SyndromeFDA approvedFemaleFoundationsGene ProteinsGenesGenetic RecombinationGenetic TranscriptionGenomeGenomicsHIVHumanIACUCIn Situ HybridizationInstitutional Review BoardsKnowledgeMethodologyModelingMolecularMolecular BiologyMolecular NeurobiologyMolecular TargetMosaicismNatureNeurofibrillary TanglesNeurogliaNeuronsNucleotidesPathogenicityPatientsPatternPrevalencePublishingRNARNA-Directed DNA PolymeraseReportingReverse Transcriptase InhibitorsRoleSamplingSenile PlaquesTestingTherapeuticToxic effectValidationVariantagedbrain tissuecell typeds-DNAfamilial Alzheimer diseasegenetic varianthuman embryonic stem cellinduced pluripotent stem cellintegration sitemalemosaicnanobodiesneurobiological mechanismneuropathologynew therapeutic targetnovelsequencing platformsextherapeutic target
项目摘要
PROJECT SUMMARY/ABSTRACT
We have identified somatic gene recombination (SGR) in neurons of the human brain, with particular relevance to sporadic Alzheimer’s disease (SAD) (Nature 563, 639-645 (2018)). This discovery represents a new and functionally significant aspect of genomic mosaicism (eLife;4:e05116 (2015)) that has genuine therapeutic potential through newly identified molecular targets. Indeed, we found that SGR, acting on the AD gene for Amyloid Precursor Protein (APP), produces thousands of distinct forms of APP, some of which are enriched in or unique to AD. The APP gene variations related to AD that were analyzed thus far include copy number variations (CNVs) and at least 11 single-nucleotide variations (SNVs) that were previously reported as pathogenic in familial AD, yet that arose somatically and mosaically in SAD; these variations were absent from non-diseased neurons. SGR utilizes reverse transcriptase (RT) activity on transcribed RNAs that, combined with DNA strand-breaks and APP gene transcription, produce double-stranded DNA that is retro-inserted back into the genome to form “genomic cDNAs” (gencDNAs). These published data contribute to the scientific foundation on which the current proposal will build, to test the hypothesis that altered SGR, involving brain-specific reverse transcriptases, functionally contributes to AD and affects multiple genes, providing novel targets for AD therapies. Postmortem IRB-approved and de-identified brain samples from validated AD donors of both sexes will be compared to non-diseased controls, while IACUC-approved animal experiments will model SGR and its AD-relevant endpoints. Three Aims will be pursued over 5 years. Aim 1 will define the molecular neurobiology of APP gencDNA diversity and identify new SGR genes enhanced in AD brains. Aim 2 will determine expression and function of SGR genes in AD brain and model systems. Aim 3 will identify genes responsible for RT SGR activity within normal and AD brains. This proposal will thus open new vistas into AD via novel SGR mechanisms and will identify new therapeutic targets for the treatment of AD.
项目总结/摘要
我们已经鉴定了人脑神经元中的体细胞基因重组(SGR),与散发性阿尔茨海默病(SAD)特别相关(Nature 563,639-645(2018))。这一发现代表了基因组镶嵌的一个新的和功能上重要的方面(eLife;4:e05116(2015)),其通过新鉴定的分子靶标具有真正的治疗潜力。事实上,我们发现SGR作用于淀粉样前体蛋白(APP)的AD基因,产生数千种不同形式的APP,其中一些是AD所特有的或富集的。到目前为止,分析的与AD相关的APP基因变异包括拷贝数变异(CNVs)和至少11个单核苷酸变异(SNVs),这些变异先前被报道为家族性AD的致病性,但在SAD中出现体细胞和镶嵌;这些变异在非患病神经元中不存在。SGR利用对转录的RNA的逆转录酶(RT)活性,其与DNA链断裂和APP基因转录结合,产生双链DNA,所述双链DNA反向插入回到基因组中以形成“基因组cDNA”(gencDNAs)。这些已发表的数据为当前提案的科学基础做出了贡献,以验证以下假设:涉及脑特异性逆转录酶的SGR改变在功能上有助于AD并影响多个基因,为AD治疗提供了新的靶点。将来自两种性别的经验证的AD供体的经IRB批准和去识别的死后脑样本与非疾病对照进行比较,而IACUC批准的动物实验将模拟SGR及其AD相关终点。五年内将实现三个目标。目的1明确APP基因cDNA多样性的分子神经生物学机制,并鉴定在AD脑中增强的新的SGR基因。目的2研究SGR基因在AD脑及模型系统中的表达及功能。目的3将确定负责正常和AD脑内RT SGR活性的基因。因此,这一提议将通过新的SGR机制为AD开辟新的前景,并将确定治疗AD的新的治疗靶点。
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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JEROLD CHUN其他文献
JEROLD CHUN的其他文献
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{{ truncateString('JEROLD CHUN', 18)}}的其他基金
New Down syndrome brain organization revealed by single-cell genomics
单细胞基因组学揭示了新的唐氏综合症大脑组织
- 批准号:
10471627 - 财政年份:2021
- 资助金额:
$ 8.38万 - 项目类别:
Transformative research on somatic gene recombination in the normal and Alzheimer's disease-related dementia brain
正常和阿尔茨海默病相关痴呆大脑体细胞基因重组的转化研究
- 批准号:
10640064 - 财政年份:2020
- 资助金额:
$ 8.38万 - 项目类别:
Altered reverse transcriptase-dependent gene diversification mechanisms in Alzheimer's disease brains
阿尔茨海默病大脑中逆转录酶依赖性基因多样化机制的改变
- 批准号:
10545795 - 财政年份:2020
- 资助金额:
$ 8.38万 - 项目类别:
Altered reverse transcriptase-dependent gene diversification mechanisms in Alzheimer's disease brains
阿尔茨海默病大脑中逆转录酶依赖性基因多样化机制的改变
- 批准号:
10550208 - 财政年份:2020
- 资助金额:
$ 8.38万 - 项目类别:
Transformative research on somatic gene recombination in the normal and Alzheimer's disease-related dementia brain
正常和阿尔茨海默病相关痴呆大脑体细胞基因重组的转化研究
- 批准号:
10021892 - 财政年份:2020
- 资助金额:
$ 8.38万 - 项目类别:
Altered reverse transcriptase-dependent gene diversification mechanisms in Alzheimer's disease
阿尔茨海默病中逆转录酶依赖性基因多样化机制的改变
- 批准号:
10509210 - 财政年份:2020
- 资助金额:
$ 8.38万 - 项目类别:
Transformative research on somatic gene recombination in the normal and Alzheimer's disease-related dementia brain
正常和阿尔茨海默病相关痴呆大脑体细胞基因重组的转化研究
- 批准号:
10260509 - 财政年份:2020
- 资助金额:
$ 8.38万 - 项目类别:
Transformative research on somatic gene recombination in the normal and Alzheimer's disease-related dementia brain
正常和阿尔茨海默病相关痴呆大脑体细胞基因重组的转化研究
- 批准号:
10400139 - 财政年份:2020
- 资助金额:
$ 8.38万 - 项目类别:
Transformative research on the normal and Alzheimer's disease brain through studies of neuronal gene recombination
通过神经元基因重组研究对正常和阿尔茨海默病大脑进行变革性研究
- 批准号:
9983245 - 财政年份:2019
- 资助金额:
$ 8.38万 - 项目类别:
Toward a human adult brain cell atlas with single-cell technologies
利用单细胞技术构建人类成人脑细胞图谱
- 批准号:
10165827 - 财政年份:2018
- 资助金额:
$ 8.38万 - 项目类别: