Genomics Core

基因组学核心

• 批准号: 10687205
• 负责人: Towfique Raj
• 金额: $ 30.7万
• 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/10687205
• 关键词: Addendum; Affect; Age of Onset; Alzheimer' s Disease; Biological Markers; Biological Models; Brain; Brain Pathology; Brain region; C9ORF72; Cell Nucleus; Cell model; Cells; Code; Communities; Computational Technique; Cytoplasm; DNA Sequence Alteration; Data; Dedications; Disease; Dissociation; Doctor of Philosophy; Event; Exons; Freezing; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; Genes; Genetic; Genomics; Goals; Human; Human Genetics; Individual; Length; Link; Maps; Measures; Messenger RNA; Meta-Analysis; Metabolism; Methods; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurology; Neurons; Neurosciences; Nonsense-Mediated Decay; Nuclear; Nuclear Export; Pathologic; Pathology; Patients; Poly A; Polyadenylation; Population; Process; RNA Splicing; RNA-Binding Proteins; Research; Research Project Grants; Resolution; Resources; Risk; Sampling; Specificity; TDP-43 aggregation; Temporal Lobe; Testing; Transcript; Vision; Work; biomarker discovery; brain tissue; cell type; dementia risk; derepression; design verification; empowerment; experimental study; frontal lobe; genetic risk factor; genetic variant; genome wide association study; genomic data; genomic locus; high resolution imaging; human imaging; human tissue; innovation; insight; knock-down; mRNA Precursor; medical schools; multimodality; novel; premature; programs; protein TDP-43; response; risk variant; single-cell RNA sequencing; specific biomarkers; 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.

项目摘要 我们提议的没有墙壁的总体目标和奇异重点是揭开 FTLD-TDP的机制。我们已经组建了一个潜水员跨学科的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，神经病学的专家 病理。我们有FTLD专家以及外界，他们带来了新的观点和关键 资源和该领域的方法。我们的团队最近也发现了一个意外的发现 TDP-43的新剪接目标，该目标为FTD提供了直接而令人惊讶的连接 人类遗传学，将是定义FTLD-TDP机制的发射垫。我们的位置 TDP-43功能障碍引起的错误切开事件很可能是最早的事件 过程。我们的愿景是创建一个专门为提供TDP-提供前所未有的访问的中心 43功能，甚至在从核us中耗尽之前。而不是人类遗传学 事后考虑或附录，我们努力将遗传学深入融合到我们的计划中 从第1天开始。我们的中心将使我们通过网络免费生成的所有数据和代码 门户包含在FTLD-不同亚型中的人类大脑的高分辨率图像 TDP在细胞分辨率下显示TDP-43定位以及一组隐形剪接 读数是不同大脑区域中TDP-43活性的敏感信标。这将授权 广泛的FTLD研究社区，以产生（和检验）有关疾病的新假设 机制并具有处置敏感生物标志物。我们的中心将推出多模式 1）全面发现与人FTLD-TDP相关的TDP-43剪接目标； 2）定义TDP-43依赖性加密外显子剪接事件的机制有助于 神经变性，使用模型系统和人体组织； 3）利用这些小说的加密货币 外显子为FTD场产生高度敏感和特定的生物标志物； 4）创新基因组学 分析方法以整合人类遗传学数据和RNA测序数据并制作这些方法 社区可用的资源，以发现FTD的遗传风险因素如何促进 加密外显子剪接，反之亦然。我们强烈怀疑我们会发现加密外显子 剪接代码可作为阿喀琉斯的脚跟，以驱动FTLD-TDP中的神经变性。