Administrative Core

行政核心

基本信息

批准号：
10687204
负责人：
Aaron D. Gitler
金额：
$ 15.2万
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/10687204
关键词：
Achievement Addendum Advisory Committees Autopsy Biological Markers Biological Models Brain Brain region Cell Nucleus Code Collaborations Communication Communities Data Decision Making Dedications Disease Doctor of Philosophy Electronic Mail Ensure Event Exons Frontotemporal Lobar Degenerations Functional disorder Genetic Genomics Geographic Locations Goals Grant Health Human Human Genetics Human Resources Induced pluripotent stem cell derived neurons Manuscripts Methods Modeling Monitor National Institute of Neurological Disorders and Stroke Nerve Degeneration Neurology Neurosciences Pathology Persons Process RNA Splicing Reporting Research Research Personnel Research Project Grants Resolution Resources Schedule Teleconferences Telephone Testing Universities Vision brain tissue data communication data sharing empowerment frontotemporal lobar dementia amyotrophic lateral sclerosis genetic risk factor high resolution imaging human imaging human tissue innovation meetings multimodality novel operation programs protein TDP-43 specific biomarkers therapeutic target transcriptome sequencing transcriptomics 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.

项目概要我们提议的无围墙中心的总体目标和单一重点是解开 FTLD-TDP 机制我们已经组建了一个多元化的跨学科团队来解决这个问题。我们的团队汇集了遗传学、基因组学、神经科学、神经病学等领域的专家。我们有 FTLD 专家以及带来新观点和关键的外部人士。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 的直接且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。由 TDP-43 功能障碍引起的错误剪接事件很可能是最早的事件我们的愿景是创建一个致力于提供前所未有的 TDP 服务的中心。 43 甚至在它从细胞核中耗尽之前就发挥了作用，而不是把人类遗传学作为一种手段。事后或附录，我们努力将遗传学深深融入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 FTLD 不同亚型的人脑高分辨率图像的门户网站 TDP 以细胞分辨率显示 TDP-43 定位以及一组隐秘剪接读数作为不同大脑区域 TDP-43 活动的敏感信标，这将增强广泛的 FTLD 研究社区生成（并测试）有关疾病的新假设机制并拥有可供使用的敏感生物标志物，我们的中心将推出多模式。努力：1）全面发现与人类FTLD-TDP相关的TDP-43剪接靶点； 2) 定义 TDP-43 依赖性神秘外显子剪接事件的机制神经退行性变，使用模型系统和人体组织；3）利用这些新颖的神秘因素外显子为 FTD 领域生成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，使这些数据社区可利用的资源来发现 FTD 的遗传风险因素如何影响神秘的外显子剪接，反之亦然，我们强烈怀疑我们会发现神秘的外显子。拼接代码是驱动 FTLD-TDP 神经退行性疾病的致命弱点。