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Principal Investigator: Li Gan
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $1,320,382
Funding agency: National Institute on Aging
PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD) is a leading cause of dementia among the elderly and the most prevalent age-
related neurodegenerative disease, affecting ~56 million individuals worldwide. Despite of its high heritability
(estimates ranging 60-80%) and many genetic variants (residing in tens of loci across the genome) identified
from genome-wide association studies (GWAS), our knowledge of the underlying genetic mechanisms remains
limited. Uncovering pathophysiological mechanisms underlying AD proves to be highly challenging. To
advance our mechanistic understanding of AD, we will first acquire and harmonize various in-house, protected
and public data, encompassing bulk and single cell RNA-seq data, GWAS summary statistics, array
genotyping and whole genome sequencing data, as well as functional genomic data. We will then analyze
them using a suite of computational methods and bioinformatics tools to generate cell-type-specific
mechanistic hypotheses. These hypotheses will be validated through experimental technologies. Our
validations will be carried out in iPSC-derived neural cells (particularly excitatory neurons and microglia), as
well as in iPSC-derived brain organoids involving diverse cell types including neurons, astrocytes, and
microglia. In these iPSC-derived cells and organoids models, we will leverage CRISPRi as well as knock-in
experimental technologies to perturb the most promising putatively causal regulatory DNA elements, and
evaluate the impact by measuring a cascade of molecular and cellular phenotypes including gene expression
and AD related physiological phenotypes.
Terms: <3-D><3-Dimensional><3D><4C-seq><AD dementia><Active Follow-up><Address><Affect><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease risk><Alzheimers Dementia><Amentia><Assay><Astrocytes><Astrocytus><Astroglia><Base Pairing><Bioassay><Biological Assay><Biological Function><Biological Process><Body Tissues><Brain><Brain Nervous System><Brain imaging><CNS Nervous System><CRISPR><CRISPR interference><CRISPR-dCas9-mediated repression><CRISPR/Cas system><CRISPR/dCas9 interference><CRISPR/dCas9-mediated transcriptional inhibition><CRISPRi><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Central Nervous System><Cerebrum><Chromatin Conformation Capture and Sequencing><Chromatin Loop><Chromatin Loop Domains><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats interference><Complex><Computational Technique><Computing Methodologies><Creativeness><DNA><DNA Loop><Data><Dementia><Deoxyribonucleic Acid><Disease><Disorder><Distal><Elderly><Elements><Encephalon><Fore-Brain><Forebrain><GWA study><GWAS><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><Gene variant><Genes><Genetic><Genetic Transcription><Genome><Genotype><Heritability><Hortega cell><Individual><Intracellular Communication and Signaling><Knock-in><Knowledge><Measurement><Measures><Mediating><Microglia><Modeling><Molecular><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurobiology><Neurocyte><Neurons><Nucleic Acid Regulator Regions><Nucleic Acid Regulatory Sequences><Organoids><Pathogenesis><Pathway interactions><Phenotype><Physiologic><Physiological><Play><Population><Primary Senile Degenerative Dementia><Prosencephalon><Protocol><Protocols documentation><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Regulation><Regulator Genes><Regulatory Regions><Resolution><Role><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><System><Techniques><Technology><Testing><Tissues><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Transcriptional Regulatory Elements><Validation><Variant><Variation><Work><active followup><advanced age><age associated neurodegeneration><age associated neurodegenerative disease><age associated neurodegenerative disorder><age dependent neurodegeneration><age dependent neurodegenerative condition><age dependent neurodegenerative disease><age dependent neurodegenerative disorder><age related neurodegeneration><age-driven neurodegenerative disorders><age-related neurodegenerative disease><age-related neurodegenerative disorder><aging associated neurodegeneration><aging associated neurodegenerative disease><aging related neurodegeneration><aging related neurodegenerative disease><aging related neurodegenerative disorder><allele variant><allelic variant><alzheimer risk><astrocytic glia><bio-informatics tool><bioinformatics tool><biological signal transduction><brain cell><brain visualization><candidate validation><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cell type><cerebral><computational methodology><computational methods><computational suite><computer based method><computer methods><computing method><creativity><differential expression><differentially expressed><entire genome><epigenomics><excitatory neuron><experiment><experimental research><experimental study><experiments><follow up><follow-up><followed up><followup><full genome><functional genomics><genetic regulatory element><genetic variant><genome sequencing><genome wide analysis><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genome wide studies><genome-wide analysis><genome-wide identification><genomewide association scan><genomewide association studies><genomewide association study><genomic data><genomic data-set><genomic dataset><genomic variant><geriatric><gitter cell><global gene expression><global transcription profile><iPS><iPSC><iPSCs><imaging genetics><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><knockin><mesoglia><microglial cell><microgliocyte><neurobiological><neuronal><pathway><perivascular glial cell><primary degenerative dementia><programs><promoter><promotor><regulatory gene><repressing CRISPR-dCas9 system><resolutions><scRNA-seq><senile dementia of the Alzheimer type><senior citizen><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><statistics><therapeutic agent development><therapeutic development><three dimensional><trans acting element><transcriptional differences><transcriptome><transcriptome sequencing><transcriptomic sequencing><transcriptomics><validations><whole genome><whole genome association analysis><whole genome association studies><whole genome association study>