Document text
Principal Investigator: Alon Goren
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $784,231
Funding agency: National Institute of Mental Health
PROJECT SUMMARY
Autism spectrum disorder (ASD), which is usually accompanied of intellectual disability (ID), is part of a group of
neurodevelopmental disorders that are usually diagnosed during the first two years of age. The social, emotional
and communication skills of affected individuals are severely impaired throughout life and are often accompanied
by a spectrum of debilitating symptoms with different degrees of severity including, stereotypic behavioral traits,
epileptic episodes, sensory oversensitivity, and impaired motor functions that seriously interfere with their daily
life activities. ASD is an important public health concern as it affects 1 in 54 individuals. It occurs in all racial,
ethnic, and socioeconomic groups, and in the United States alone, the estimated total cost per year per children
is between $11.5 and $60.9 billion. Thus, families with ID/ASD-diagnosed children experience heavy
psychological and financial burdens. While early intervention services can significantly improve certain aspects
of child's development, no disease-modifying treatments are currently available. Despite enormous efforts, lack
of effective therapies is likely due to our poor understanding of the molecular and cellular mechanisms underlying
these conditions with exceedingly complex etiology. The number of different types of genetic variations
associated with ASD keeps increasing thanks to the improvement in genomic sequencing technology. However,
there is still little understanding of how these genetic changes impact cellular and molecular pathways or which
brain cell are more affected by these mutations that ultimately result in brain dysfunction associated with ASD.
Among them, loss-of-function genetic variations in the SETD5 gene, which is believe to play an important role in
the structure of the genome and in regulating expression of neuronal genes. However, there are important
knowledge gaps on the molecular and cellular pathways controlled by SETD5 and how ASD-related mutations
in this gene could contribute to neuronal dysfunction. We and others started to address these questions by
generating Setd5 deficient mice and showed impaired neuronal function and appearance of ASD-like behaviors.
However, mouse models are limited to accurately recapitulate not only disease pathologies but also the
protracted process of human brain development. Thus, they can lead to misleading hypothesis. To compensate
for these limitations, we have modeled for the first time SETD5-related ASD using human induced pluripotent
stem cells (hiPSC). Generating neurons from these cells we recapitulated neuronal dysfunction as previously
observed in mice models. More importantly, we uncovered new mechanisms inducing this neuronal dysfunction.
In particular, we found that astrocytes, which are more abundant and necessary for keeping neurons healthy
and connected in the brain, might produce neurotoxic activity. In this proposal, we extensively characterize the
molecular and cellular pathways involved in this process and explore novel therapeutic targets to revert or
prevent neuronal dysfunction induced by SETD5 mutations. The successful completion of this research will
provide an unprecedented view of astrocyte involvement in ASD and potentially revolutionize its treatment.
Terms: <0-11 years old><2 year old><2 years of age><ASD><ATAC sequencing><ATAC-seq><ATACseq><Acute><Address><Affect><Antisense Agent><Antisense Oligonucleotides><Appearance><Assay><Assay for Transposase-Accessible Chromatin using sequencing><Astrocytes><Astrocytus><Astroglia><Attenuated><Autism><Autistic Disorder><Automobile Driving><Autoregulation><B-Cell Differentiation Factor Gene><B-Cell Stimulatory Factor 2 Gene><BSF-2 Gene><BSF2 Gene><Behavior><Behavioral><Beta-2 Gene Interferon><Binding><Bioassay><Biochemical><Biological Assay><Brain><Brain Nervous System><CRISPR activation><CRISPR activator><CRISPR approach><CRISPR based activation><CRISPR based approach><CRISPR gene activation><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR transcription activation><CRISPR transcriptional activation><CRISPR-CAS-9><CRISPR-Cas-9-mediated gene activation><CRISPR-based gene activation><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR-dCAS9 Activator><CRISPR-mediated transcriptional activation><CRISPR/CAS approach><CRISPR/CAS9 activation><CRISPR/CAS9 gene activation><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><CRISPR/dCas9 activation><CRISPR/dCas9-based transcriptional activation><CRISPRa><Cas nuclease technology><Catalogs><Causality><Cell Body><Cells><ChIP Sequencing><ChIP-seq><ChIPseq><Child><Child Development><Child Youth><Children (0-21)><Chromatin><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Communication><Communication challenge><Communication difficulty><Compensation><Complex><Defect><Development><Diagnosis><Disease><Disorder><Disturbance in cognition><Drug Screening><Dysfunction><EC 2.1.1><Early Infantile Autism><Early Intervention><Electrophysiology><Electrophysiology (science)><Emotional><Encephalon><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epilepsy><Epileptic Seizures><Epileptics><Ethnic Origin><Ethnicity><Etiology><Failure><Family><Financial Hardship><Functional disorder><GRO-seq><GROseq><Gene Targeting><Gene variant><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Diversity><Genetic Variation><Genetic defect><Genome><Genomics><Goals><HSF Gene><Hepatocyte Stimulatory Factor Gene><Heterogeneity><Histones><Homeostasis><Human><Human Development><Hybridoma Growth Factor Gene><IFNB2 Gene><IL-6 Gene><IL6><IL6 gene><Impaired cognition><Impairment><In Vitro><Individual><Induced Neurons><Infant and Child Development><Infantile Autism><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Interleukin 6 (Interferon, Beta 2) Gene><Interleukin-6 Gene><Interpersonal Interaction><Interpersonal Relations><JAK kinase><Janus kinase><Kanner's Syndrome><Knowledge><L-Lysine><Life><Link><Lysine><Mediating><Methods><Methyltransferase><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Motor><Murine><Mus><Mutate><Mutation><N-CoR protein><NCOR1><NCOR1 gene><NCoR protein><NPC><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurodevelopmental Disorder><Neurological Development Disorder><Neuronal Dysfunction><Neurons><Neurophysiology / Electrophysiology><Nuclear Pore Complex><Nuclear Receptor Corepressor 1><Optics><Outcome><Paf1><Pathology><Pathway interactions><Physiological Homeostasis><Physiology><Physiopathology><Play><Process><Public Health><RIP13 protein><RNA Processing><Race><Races><Recovery><Regulator Genes><Research><Risk-associated variant><Role><SET Domain><Seizure Disorder><Sensory><Severities><Stereotyping><Structure><System><Technology><Testing><Therapeutic><Therapeutic Intervention><Time><Transcription Elongation><Transcriptional Regulatory Elements><Translations><United States><Visualization><abnormal brain function><activating CRISPR technology><age 2 years><aged 2 years><aged two years><allele variant><allelic variant><antisense oligo><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><astrocytic glia><attenuate><attenuates><attenuation><autism attributes><autism indicator><autism spectral disorder><autism spectrum disorder><autism spectrum disorder features><autism spectrum disorder indicator><autism spectrum disorder symptoms><autism symptomology><autism symptoms><autism-like symptoms><autism-related attributes><autistic features><autistic spectrum disorder><autistic symptoms><autistic traits><autistic-like symptoms><brain cell><brain dysfunction><brain impairment><catalog><causation><chromatin immunoprecipitation-sequencing><chromatin remodeling><cognitive dysfunction><cognitive loss><cost><debilitating symptom><design><designing><developmental><disease causation><disease risk><disorder risk><driving><dysfunctional brain><effective therapy><effective treatment><electrophysiological><epigenetically><epilepsia><epileptogenic><experience><financial adversity><financial burden><financial distress><financial insecurity><financial strain><financial stress><genetic variant><genome editing><genome mutation><genomic editing><genomic tools><genomic variant><global run on sequencing><global run on transcription sequencing><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iNeuron><improved><induced human pluripotent stem cells><intellectual and developmental disability><interpersonal relationship><intervention therapy><kids><kinase inhibitor><limited intellectual functioning><loss of function><methylase><motor impairment><mouse model><movement impairment><movement limitation><multiomics><multiple omics><murine model><neural><neural dysfunction><neurodevelopmental disease><neuron toxicity><neuronal><neuronal toxicity><neurotoxic><neurotoxicity><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><nuclear receptor co-repressor><optical><pancreatic differentiation 2><pancreatic differentiation 2 protein><panomics><pathophysiology><pathway><pharmacologic><polymerase associated factor 1><prevent><preventing><psychologic><psychological><racial><racial background><racial origin><regulatory gene><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><scRNA-seq><service intervention><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skills><social><social role><socio-economic><socio-economically><socioeconomically><socioeconomics><synapse formation><synaptogenesis><therapeutic target><tool><trait><trans acting element><translation><transmethylase><two year old><two years of age><youngster>