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

• 批准号: 10295436
• 负责人: Pietro Fratta
• 金额: $ 172.2万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/10295436
• 关键词: Addendum; Amyloid beta-Protein; Antibodies; Antigens; Biochemical; Biological Markers; Biological Models; Brain; Brain Diseases; Brain region; Cell Nucleus; Code; Communities; Cytomegalovirus Infections; Cytoplasm; Data; Disease; Event; Exons; Frontotemporal Dementia; Functional disorder; Genes; Genetic; Genomics; Goals; Human; Human Genetics; Link; Messenger RNA; Methods; Molecular Weight; Monoclonal Antibodies; Mutation; 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; Testing; Toxic effect; Ubiquitin; Virginia; Vision; alpha synuclein; disease classification; 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

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.

项目总结