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Principal Investigator: Stefan Aigner
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $787,592
Funding agency: National Institute of Mental Health
PROJECT SUMMARY
Autism spectrum disorder (ASD) is a clinically complex, heterogeneous condition affecting 1 in 44 children in the
U.S. The identification of common etiologies across multiple forms of genetic and idiopathic forms of ASD will
critically advance diagnostic biomarker discovery and therapeutic development. Dysregulation of cellular
translation has emerged as a pathophysiological mechanism common to at least a subset of ASD forms.
However, systematic investigation of the cellular mechanisms that converge onto the ASD phenotype has been
hampered by a paucity of robust and reproducible human ASD cellular models and scalable experimental tools
for cell-type resolved characterization at the level of translation. To address these bottlenecks and to directly
address the role of translational dysregulation as a common feature in ASD, we have (1) used advanced genome
engineering tools to generate an extensively validated, isogenic series of induced pluripotent stem cell (iPSC)
lines modeling 15 syndromic forms of ASD caused by highly penetrant gene and genome variants, representing
~10% of the total ASD population (the largest such panel created to date, to our knowledge), (2) established a
robust human iPSCs-derived cortical organoid model of brain development, and (3) developed ribo-STAMP, a
method for translational profiling of individual cells in heterogeneous cell populations, which is the first and only
method enabling translation to be measured at single- cell resolution. In this project, we identify common and
divergent pathological mechanisms in genome- engineered isogenic stem cell based organoid models of ASD,
using single-cell transcriptomic and translatomic approaches. We validate our findings using cellular and
functional phenotypic assays and in patient-derived iPSC models. If successful, our study will identify common
and unique translation-aware single-cell resolved gene expression signatures that predict cellular and functional
outcomes. We anticipate that our datasets and insights into cell-type specific deficits in gene expression of
genetic forms of autism will critically accelerate the development of a unified framework that enables molecular
categorization of both genetic and idiopathic cases, facilitating the identification of biomarkers and the
development of targeted therapies.
Terms: <0-11 years old><3-D><3-Dimensional><3D><APOBEC-1><APOBEC1><ASD><Acceleration><Address><Affect><Apobec-1 protein><Architecture><Assay><Autism><Autistic Disorder><Autopsy><Awareness><BEDP><Bioassay><Biological Assay><Body Tissues><Brain><Brain Nervous System><CDAR1><Calcium><Categories><Causality><Cell Body><Cell Communication and Signaling><Cell Line><Cell Signaling><Cell model><CellLine><Cells><Cellular model><Child><Child Youth><Children (0-21)><Chromium><Chromosomal microdeletion><Chromosome Mapping><Clinical><Complex><Connector Neuron><Copy Number Polymorphism><Corpus Striatum><Corpus striatum structure><Cr element><Data><Data Set><Defect><Development><Early Infantile Autism><Encephalon><Engineering / Architecture><Enzyme Gene><Enzymes><Etiology><Expression Signature><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Fore-Brain><Forebrain><Frequencies><Gene Expression><Gene Expression Profile><Gene Localization><Gene Mapping><Gene Mapping Genetics><Gene Transcription><Genes><Genetic><Genetic Models><Genetic Transcription><Genome><Genome engineering><HEPR><Human><Image><Individual><Infantile Autism><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><Investigation><Investigators><Kanner's Syndrome><Linkage Mapping><Measures><Mechanistic Target of Rapamycin><Messenger RNA><Methodology><Methods><Modeling><Modern Man><Molecular><Nature><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurodevelopmental Disorder><Neurological Development Disorder><Neurons><Noise><Operative Procedures><Operative Surgical Procedures><Organoids><Pathologic><Pathology><Pathway interactions><Patients><Phenotype><Population><Progenitor Cells><Prosencephalon><Protein Biosynthesis><Proteins><RAFT1><RNA Editing><RNA Expression><RNA, Messenger, Editing><Rabies mapping><Rabies trans synaptic tracing><Rabies virus mediated mapping><Rapamune><Rapamycin><Recurrence><Recurrent><Regulation><Reproducibility><Research Personnel><Research Resources><Researchers><Resolution><Resources><Ribosomal Interaction><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Ribosomal Proteins><Ribosomes><Risk-associated variant><Role><Series><Signal Transduction><Signal Transduction Systems><Signaling><Sirolimus><Site><Strains Cell Lines><Striate Body><Striatum><Surgical><Surgical Interventions><Surgical Procedure><Synapses><Synaptic><Testing><Tissues><Total Human and Non-Human Gene Mapping><Transcription><Translations><Variant><Variation><apoB mRNA editing catalytic subunit><apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1><autism model><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><biological signal transduction><biomarker discovery><biomarker identification><brain tissue><candidate validation><causation><cell type><copy number variant><copy number variation><cultured cell line><developmental><diagnostic biomarker><diagnostic development><diagnostic marker><disease causation><disease model><disease risk><disorder model><disorder risk><drug detection><drug testing><functional outcomes><gene expression pattern><gene expression signature><genetic mapping><global gene expression><global transcription profile><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS><iPSC><iPSCs><identification of biomarkers><identification of new biomarkers><imaging><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><inducible pluripotent stem cell><insight><kids><mRNA><mTOR><mammalian target of rapamycin><marker identification><microdeletion><migration><model of autism spectrum disorder><multi-electrode arrays><multielectrode arrays><necropsy><neurodevelopmental disease><neuronal><neuronal circuit><neuronal circuitry><pathway><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient-derived pluripotent stem cells><pharmacologic><postmortem><predictive signature><progenitor cell model><progenitor model><protein synthesis><rabies based mapping><rabies based retrograde mapping><rabies circuit tracing><rabies mediated retrograde monosynaptic tracing><rabies retrograde tracing><rabies tracer><rabies tracing><rabies viral tracing><rabies virus mediated circuit mapping><rabies virus monosynaptic circuit tracing><rabies virus monosynaptic tracing><rabies virus retrograde tracing><rabies virus tracing><resolutions><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stable cell line><stem and progenitor cell model><stem cell based model><stem cell derived model><stem cell model><stem cells><striatal><surgery><synapse><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic agent development><therapeutic development><three dimensional><tool><tracing with rabies><transcriptional profile><transcriptional signature><transcriptome><transcriptomics><transgene expression><translation><translatome><youngster>