Genomics Core
基因组学核心
基本信息
- 批准号:10687205
- 负责人:
- 金额:$ 30.7万
- 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:2021-09-15 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddendumAffectAge of OnsetAlzheimer&aposs DiseaseBiological MarkersBiological ModelsBrainBrain PathologyBrain regionC9ORF72Cell NucleusCell modelCellsCodeCommunitiesComputational TechniqueCytoplasmDNA Sequence AlterationDataDedicationsDiseaseDissociationDoctor of PhilosophyEventExonsFreezingFrontotemporal DementiaFrontotemporal Lobar DegenerationsFunctional disorderGenesGeneticGenomicsGoalsHumanHuman GeneticsIndividualLengthLinkMapsMeasuresMessenger RNAMeta-AnalysisMetabolismMethodsMolecularNerve DegenerationNeurodegenerative DisordersNeurogliaNeurologyNeuronsNeurosciencesNonsense-Mediated DecayNuclearNuclear ExportPathologicPathologyPatientsPoly APolyadenylationPopulationProcessRNA SplicingRNA-Binding ProteinsResearchResearch Project GrantsResolutionResourcesRiskSamplingSpecificityTDP-43 aggregationTemporal LobeTestingTranscriptVisionWorkbiomarker discoverybrain tissuecell typedementia riskderepressiondesign verificationempowermentexperimental studyfrontal lobegenetic risk factorgenetic variantgenome wide association studygenomic datagenomic locushigh resolution imaginghuman imaginghuman tissueinnovationinsightknock-downmRNA Precursormedical schoolsmultimodalitynovelprematureprogramsprotein TDP-43responserisk variantsingle-cell RNA sequencingspecific biomarkerstherapeutic targettranscriptome sequencingweb portal
项目摘要
Project Summary
The overall goal and singular focus of our proposed Center Without Walls is to unravel the
mechanisms of FTLD-TDP. We have formed a diverse interdisciplinary team to tackle this
challenge. Our team brings together experts in genetics, genomics, neuroscience, neurology, and
pathology. We have FTLD experts as well as outsiders who bring new perspectives and key
resources and approaches to the field. Our team has also recently made an unexpected discovery
of a new splicing target of TDP-43, which provides a direct and surprising connection to FTD
human genetics and will be a launching pad for defining the mechanisms of FTLD-TDP. We posit
that mis-splicing events caused by TDP-43 dysfunction may well be the earliest events in the
process. Our vision is to create a Center dedicated to providing unprecedented access to TDP-
43 function, even before it is depleted from the nucleus. Rather than have human genetics as an
afterthought or addendum, we endeavor to have the genetics deeply integrated in our program
from Day 1. Our Center will make all of the data and code we generate freely available via a web
portal that contains high resolution images of human brains across different subtypes of FTLD-
TDP showing, at cellular resolution, TDP-43 localization along with a panel of cryptic splicing
readouts as sensitive beacons of TDP-43 activity in different brain regions. This will empower the
broad FTLD research community to generate (and test) new hypotheses about disease
mechanisms and to have at their disposal sensitive biomarkers. Our Center will launch multimodal
efforts to 1) comprehensively discover the TDP-43 splicing targets relevant to human FTLD-TDP;
2) define the mechanisms by which TDP-43-dependent cryptic exon splicing events contribute to
neurodegeneration, using model systems and human tissues; 3) harness these novel cryptic
exons to generate highly sensitive and specific biomarkers for the FTD field; 4) innovate genomics
analysis methods to integrate human genetics data and RNA sequencing data and make these
resources available to the community to discover how genetic risk factors for FTD contribute to
cryptic exon splicing and vice versa. We strongly suspect that we will discover the cryptic exon
splicing code that serves as the Achilles’ heel to drive neurodegeneration in FTLD-TDP.
项目摘要
我们提议的无墙中心的总体目标和唯一重点是拆解
FTLD-TDP的机理。我们已经组建了一个不同的跨学科团队来解决这个问题
挑战。我们的团队汇集了遗传学、基因组学、神经科学、神经学和
病理学。我们有FTLD专家以及外部人士,他们带来了新的视角和关键
实地的资源和方法。我们的团队最近也有了一个意想不到的发现
TDP-43的新剪接靶标,它提供了与FTD的直接和令人惊讶的连接
人类遗传学,并将成为定义FTLD-TDP机制的发射台。我们假设
TDP-43功能障碍导致的错误剪接事件很可能是
进程。我们的愿景是创建一个致力于提供前所未有的TDP访问的中心-
43功能,甚至在它从细胞核中耗尽之前。而不是把人类遗传学作为
经过深思熟虑或补充,我们努力将遗传学深度整合到我们的计划中
从第一天开始。我们的中心将通过网络免费提供我们生成的所有数据和代码
包含不同FTLD亚型的人脑高分辨率图像的门户-
TDP在细胞分辨率下显示TDP-43的定位以及一组神秘的剪接
读数作为不同脑区TDP-43活动的灵敏信标。这将使
广泛的FTLD研究社区生成(和测试)关于疾病的新假说
机制,并拥有敏感的生物标记物。我们中心将推出多式联运
努力1)全面发现与人FTLD-TDP相关的TDP-43剪接靶点;
2)定义依赖TDP-43的隐蔽外显子剪接事件的作用机制
神经退化,使用模型系统和人体组织;3)利用这些新的神秘
外显子为FTD领域产生高度敏感和特异的生物标记物;4)创新基因组学
整合人类遗传学数据和RNA测序数据的分析方法,并使这些
社区可用的资源,以发现FTD的遗传风险因素如何有助于
神秘的外显子拼接,反之亦然。我们强烈怀疑我们将发现神秘的外显子
剪接密码是FTLD-TDP中驱动神经退化的致命弱点。
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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