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Discovery of novel TDP-43 splicing targets: the Achilles heel for FTD and towards sensitive biomarkers and therapeutic targets

发现新型 TDP-43 剪接靶点：FTD 以及敏感生物标志物和治疗靶点的致命弱点

基本信息

批准号：
10687203
负责人：
Pietro Fratta
金额：
$ 159.75万
依托单位：
STANFORD UNIVERSITY
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：
https://reporter.nih.gov/project-details/10687203
关键词：
Addendum Alzheimer&apos s Disease Amyloid beta-Protein Antibodies Antigens Biochemical Biological Markers Biological Models Brain Brain Diseases Brain region Cell Nucleus Code Communities Cytomegalovirus Infections Cytoplasm Data Dedications Disease Event Exons Frontotemporal Dementia Frontotemporal Lobar Degenerations Functional disorder Genes Genetic Genomics Goals Human Human Genetics Link Messenger RNA Methods Molecular Weight Monoclonal Antibodies Mutation Names Nerve Degeneration Neurodegenerative Disorders Neurology Neurosciences Nuclear Nuclear Protein Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology PrP Prion Diseases Process Proteins RNA Splicing RNA Transport RNA metabolism RNA-Binding Proteins Research Resolution Resources Role Sagittaria TDP-43 aggregation Testing Toxic effect Ubiquitin Virginia Vision alpha synuclein disease classification empowerment gain of function genetic risk factor high resolution imaging human disease human imaging human tissue innovation misfolded protein multimodality new therapeutic target novel polyglutamine programs protein TDP-43 protein aggregation specific biomarkers tau Proteins therapeutic target transcriptome sequencing web 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.

项目摘要我们提出的无墙中心的总体目标和单一重点是解开 FTLD-TDP的机制。我们组建了一支多元化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、神经病学和病理我们有FTLD专家以及外部人士，他们带来了新的观点和关键资源和外地办法。我们的团队最近还意外地发现 TDP-43的一个新的剪接靶点，它提供了与FTD的直接和令人惊讶的联系，人类遗传学，并将成为定义FTLD-TDP机制的发射台。我们断定由TDP-43功能障碍引起的错误拼接事件很可能是最早的事件过程我们的愿景是创建一个中心，致力于提供前所未有的访问TDP- 43功能，甚至在它从核中耗尽之前。而不是把人类遗传学作为事后的想法或补充，我们奋进有遗传学深入融入我们的计划从第一天开始。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网站- TDP显示，在细胞分辨率下，TDP-43定位沿着一组隐蔽剪接作为TDP-43在不同大脑区域活动的敏感信标。这将使广泛的FTLD研究社区，以产生（和测试）关于疾病的新假设机制，并拥有敏感的生物标志物。我中心将推出多式联运 1）全面发现与人FTLD-TDP相关的TDP-43剪接靶点; 2)明确TDP-43依赖性隐蔽外显子剪接事件有助于神经变性，使用模型系统和人体组织; 3）利用这些新的隐蔽的外显子，为FTD领域产生高度敏感和特异性的生物标志物; 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，社区现有的资源，以发现FTD的遗传风险因素如何促成隐蔽外显子剪接，反之亦然。我们强烈怀疑我们会发现隐藏的外显子剪接代码，其充当驱动FTLD-TDP中神经变性的阿喀琉斯之踵。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes.

DOI：
10.1007/s00401-023-02583-z
发表时间：
2023-07
期刊：
ACTA NEUROPATHOLOGICA
影响因子：
12.7
作者：
Fodder, Katherine;Murthy, Megha;Rizzu, Patrizia;Toomey, Christina E. E.;Hasan, Rahat;Humphrey, Jack;Raj, Towfique;Lunnon, Katie;Mill, Jonathan;Heutink, Peter;Lashley, Tammaryn;Bettencourt, Conceicao
通讯作者：
Bettencourt, Conceicao

Creation of de novo cryptic splicing for ALS/FTD precision medicine.

为 ALS/FTD 精准医学创建从头神秘剪接。

DOI：
10.1101/2023.11.15.565967
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Wilkins,OscarG;Chien,MaxZYJ;Wlaschin,JosetteJ;Pisliakova,Maria;Thompson,David;Digby,Holly;Simkin,RebeccaL;Diaz,JuanAntinao;Mehta,PujaR;Keuss,MatthewJ;Zanovello,Matteo;Brown,Anna-Leigh;Harley,Peter;Darbey,Annalucia;Kard
通讯作者：
Kard

The era of cryptic exons: implications for ALS-FTD.