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Circular RNAs and their interactions with RNA-binding proteins to modulate AD-related neuropathology

环状RNA及其与RNA结合蛋白的相互作用调节AD相关神经病理学

基本信息

批准号：
10682571
负责人：
Benjamin L Wolozin
金额：
$ 61.51万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
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：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682571
关键词：
3-Dimensional Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Amyotrophic Lateral Sclerosis Astrocytes Atlases Binding Binding Proteins Binding Sites Biogenesis Biology Brain Brain region C9ORF72 Code Data Deposition Diagnosis Disease Elements Evaluation Exhibits Exons Experimental Designs Frontotemporal Dementia Frontotemporal Lobar Degenerations Functional disorder Future Gene Expression Profile Gene Proteins Genes Genetic Genetic Diseases Genetic Polymorphism Genetic Risk Genome Genomics Human Informatics Investigation Late Onset Alzheimer Disease Link Mediating Messenger RNA Methods MicroRNAs Microglia Molecular Mutation Nerve Degeneration Neurons Nucleotides Organoids Pathology Pattern Porifera Process Production Protein Isoforms Proteins Proteomics Publishing Quantitative Trait Loci RNA RNA Binding RNA Splicing RNA metabolism RNA-Binding Proteins Recording of previous events Regulation Research Design Ribosomal RNA Site Spliced Genes Susceptibility Gene System Tissues Untranslated RNA Variant Work age related axonal degeneration circular RNA crosslinking and immunoprecipitation sequencing frontotemporal lobar dementia amyotrophic lateral sclerosis genetic variant genome wide association study genome-wide genomic data genomic locus high throughput screening knock-down multi-ethnic neuropathology novel novel marker prevent protein TDP-43 protein aggregation protein metabolism stathmin synaptic function tau Proteins therapeutic target transcriptome sequencing

项目摘要

SUMMARY New variants, especially in non-coding regions, are expected to be discovered through the ongoing AD Sequencing Project (ADSP). This proposal will investigate circular RNAs (circRNAs) and RNA binding proteins (RBPs) that regulate or are regulated by these circRNAs. Recent genomic studies have discovered thousands of circRNAs produced from both protein-coding genes and non-coding regions of the genome via a process known as back-splicing. CircRNAs are more enriched in neuronal tissues and are often derived from genes specific for neuronal and synaptic function. The discovery of these circRNAs demands a coordinated investigation of RBPs that interact with the circRNAs. Mutations in and dysfunction of RBPs are known to be major mechanisms contributing to the pathophysiology in frontotemporal dementia, ALS and AD. However, the contributions of the circRNA:RBP network to these disease mechanisms are largely unknown. The novel biology of circRNAs opens an entirely new window into mechanisms of neurodegeneration in ADRD. CircRNAs could contribute to neurodegeneration by acting as sponges that sequester miRNA/RBPs away from normal mRNA targets, altering splicing or expression. RBPs also regulate circRNA production by binding to the flanking intronic sequences of circRNAs which contain many conserved binding sites of splicing factors/RBPs. Thus, sequestration of RBPs in protein aggregates could cause dysfunctional regulation of circRNAs. The history of genomics indicate that discovery of each new nucleotide species expands our understanding of disease mechanisms. The discovery of circRNA presents a major unexplored avenue of RNA metabolism that demands investigation. We hypothesize that changes in the levels of circRNAs contributes to the pathophysiology of ADRD, and that discovery of key circRNAs or circRNA-RBP interactions in aging human brains could uncover novel biomarkers, disease mechanisms or therapeutic targets. In this proposal, by leveraging large public and our own RNA-seq data (rRNA-depleted), we will apply several methods to detect and characterize AD-related circRNAs from multiple human brain regions, and integrate them with ADSP genetic findings (Aim 1). In Aim 2, aside from discovering AD-related RBPs from human brain RNA-seq, proteomics and ADSP WES/WGS data, we will leverage the ENCODE CLIP-seq data for RBP binding to identify putative RBP-circRNA interactions with AD, i.e. AD-related functional RNA elements. Finally, in Aim 3, we will select the top 10% of the circRNAs (~200) and RBPs (~150) for further high-throughput functional evaluation with a novel, powerful 3D human organoid model of ADRD, termed AstAD that exhibits the full range of tau pathology and neurodegeneration. We anticipate that our integrative analyses of ADSP genetics, circRNA, mRNA, RBP and the high-throughput AstAD functional screen readouts can help generate testable hypothesis for future molecular mechanisms experimental design.

总结

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）

Accumulation of m6A exhibits stronger correlation with MAPT than β-amyloid pathology in an APPNL-G-F /MAPTP301S mouse model of Alzheimer's disease.

在阿尔茨海默病的 APPNL-G-F /MAPTP301S 小鼠模型中，m6A 的积累与 MAPT 的相关性强于与 β-淀粉样蛋白病理学的相关性。

DOI：
10.21203/rs.3.rs-2745852/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Jiang,Lulu;Roberts,Rebecca;Wong,Melissa;Zhang,Lushuang;Webber,ChelseaJoy;Kilci,Alper;Jenkins,Matthew;Sun,Jingjing;Sun,Guangxin;Rashad,Sherif;Dedon,PeterC;Daley,SarahAnne;Xia,Weiming;Ortiz,AlejandroRondón;Dorrian,Luke;Sait
通讯作者：
Sait

Cell-type-specific expression quantitative trait loci associated with Alzheimer disease in blood and brain tissue.

DOI：
10.1038/s41398-021-01373-z
发表时间：
2021-04-27
期刊：
Translational psychiatry
影响因子：
6.8
作者：
Patel D;Zhang X;Farrell JJ;Chung J;Stein TD;Lunetta KL;Farrer LA
通讯作者：
Farrer LA

Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress.

DOI：
10.1126/sciadv.add9789
发表时间：
2023-02-03
期刊：
Science advances
影响因子：
13.6
作者：
通讯作者：

Bulk brain tissue cell-type deconvolution with bias correction for single-nuclei RNA sequencing data using DeTREM.

使用DEDREM对单核RNA测序数据进行偏置校正的散装脑组织细胞型反卷积。

DOI：
10.1186/s12859-023-05476-w
发表时间：
2023-09-19
期刊：
BMC BIOINFORMATICS
影响因子：
3
作者：
O'Neill, Nicholas K.;Stein, Thor D.;Hu, Junming;Rehman, Habbiburr;Campbell, Joshua D.;Yajima, Masanao;Zhang, Xiaoling;Farrer, Lindsay A.
通讯作者：
Farrer, Lindsay A.

TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau.

DOI：
10.1073/pnas.2014188118
发表时间：
2021-03-02
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Ash PEA;Lei S;Shattuck J;Boudeau S;Carlomagno Y;Medalla M;Mashimo BL;Socorro G;Al-Mohanna LFA;Jiang L;Öztürk MM;Knobel M;Ivanov P;Petrucelli L;Wegmann S;Kanaan NM;Wolozin B
通讯作者：
Wolozin B