Document text
Principal Investigator: Benjamin L Wolozin
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2024
Award: $610,029
Funding agency: National Institute on Aging
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.
Terms: <3-D><3-Dimensional><3D><AD dementia><AD model><AD related dementia><ADRD><Affect><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's and related dementias><Alzheimer's brain><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease brain><Alzheimer's disease model><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Alzheimers Dementia><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Amyotrophic lateral sclerosis and frontotemporal degeneration><Amyotrophic lateral sclerosis and frontotemporal dementia><Astrocytes><Astrocytus><Astroglia><Atlases><Binding><Binding Proteins><Binding Sites><Biogenesis><Biology><Body Tissues><Brain><Brain Nervous System><Brain region><C9ORF72><CLIP-Seq><Code><Coding System><Combining Site><Data><Deposit><Deposition><Diagnosis><Disease><Disorder><Dysfunction><Elements><Encephalon><Evaluation><Exhibits><Exons><Experimental Designs><Expression Signature><FTD/ALS><FTLD><FTLD/ALS><Frontal Temporal Dementia><Frontotemporal Dementia><Frontotemporal Lobar Degeneration/Amyotrophic lateral sclerosis><Frontotemporal Lobar Degenerations><Frontotemporal variety lobar degeneration><Functional RNA><Functional disorder><Future><GWA study><GWAS><Gehrig's Disease><Gene Expression Profile><Gene Proteins><Gene Splicing><Gene variant><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic Polymorphism><Genetic Risk><Genetic defect><Genome><Genomics><HITS-CLIP><High Throughput Assay><High-throughput sequencing of CLIP cDNA library><History><Hortega cell><Human><Informatics><Investigation><Isoforms><Lap18 protein><Late Onset Alzheimer Disease><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Lou Gehrig Disease><MT-bound tau><Mediating><Messenger RNA><Methods><Micro RNA><MicroRNAs><Microglia><Modern Man><Molecular><Molecular Interaction><Mutation><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neurocyte><Neuron Degeneration><Neurons><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleotides><Organoids><Origin of Life><Pathology><Pattern><Physiopathology><Porifera><Predisposition gene><Primary Senile Degenerative Dementia><Process><Production><Protein Binding><Protein Gene Products><Protein Isoforms><Proteins><Proteomics><Publishing><QTL><Quantitative Trait Loci><RNA><RNA Binding><RNA Gene Products><RNA Seq><RNA Splicing><RNA bound><RNA metabolism><RNA sequencing><RNA-Binding Proteins><RNAseq><Reactive Site><Recording of previous events><Regulation><Research Design><Ribonucleic Acid><Ribosomal RNA><Site><Spliced Genes><Splicing><Sponges><Study Type><Susceptibility Gene><System><TAR DNA-binding protein 43><TDP-43><TDP43><Tissues><Untranslated RNA><Variant><Variation><Work><age associated><age correlated><age dependent><age linked><age related><age specific><allele variant><allelic variant><alzheimer model><amyotrophic lateral sclerosis with frontotemporal dementia><amyotrophic lateral sclerosis/FTLD><amyotrophic lateral sclerosis/frontotemporal dementia><amyotrophic lateral sclerosis/ftd><astrocytic glia><axonal degeneration><bound protein><chromosome 9 open reading frame 72><circular RNA><closed circular RNA><crosslinking and immunoprecipitation sequencing><degenerative axon><front temporal dementia><frontal lobe dementia><frontotemporal dementia-amyotrophic lateral sclerosis><frontotemporal lobar dementia><frontotemporal lobar dementia amyotrophic lateral sclerosis><frontotemporal lobe degeneration associated with dementia><gene expression pattern><gene expression signature><gene locus><genetic condition><genetic disorder><genetic locus><genetic variant><genome mutation><genome scale><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genome-wide><genomewide><genomewide association scan><genomewide association studies><genomewide association study><genomic data><genomic data-set><genomic dataset><genomic location><genomic locus><genomic variant><gitter cell><high throughput screening><histories><insoluble aggregate><knock-down><knockdown><late onset alzheimer><leukemia-associated phosphoprotein p18><mRNA><mesoglia><metablastin><miRNA><miRNAs><microglial cell><microgliocyte><microtubule bound tau><microtubule-bound tau><multi-ethnic><multiethnic><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal><neuronal degeneration><neuropathologic><neuropathological><neuropathology><new marker><noncoding><novel><novel biomarker><novel marker><oncoprotein 18><pathophysiology><perivascular glial cell><phosphoprotein p18><phosphoprotein p19><polymorphism><predisposing gene><prevent><preventing><primary degenerative dementia><prosolin><protein TDP-43><protein TDP43><protein aggregate><protein aggregation><protein metabolism><rRNA><senile dementia of the Alzheimer type><stathmin><study design><susceptibility allele><susceptibility locus><susceptibility variant><synapse function><synaptic function><tau><tau Proteins><tau factor><therapeutic target><three dimensional><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><whole genome association analysis><whole genome association studies><whole genome association study><τ Proteins>