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Principal Investigator: Peng Jiang
Organization: RUTGERS, THE STATE UNIV OF N.J.
Fiscal Year: 2024
Award: $404,253
Funding agency: National Institute of Neurological Disorders and Stroke
Down syndrome (DS), caused by triplication of human chromosome 21 (HSA21), is the most common genetic
origin of intellectual disability. Studying DS disease mechanism is challenging because functional human DS
brain tissues are scarcely available and transgenic mouse models of DS demonstrate incomplete/inaccurate
expression of HSA21 genes. The advent of human induced pluripotent stem cell (hiPSC) technology has led to
the generation of DS patient-derived hiPSCs, which presents an unprecedented opportunity for studying the
pathogenesis of DS with unlimited human brain cells in vitro. While using the hiPSC-based in vitro models, basic
aspects of the disease phenotypes can be examined, the disruption of neural circuits in the developing brain
under disease conditions remains to be studied with hiPSCs. Ultimately, specific developmental and disease
mechanisms can only be modeled in live animals to identify links between cellular phenotypes and behavioral
performance. Therefore, we propose to employ hiPSC-based chimeric mouse brain models to study the
neuropathophysiology of DS in vivo. Microglia play critical roles in brain development and are also an active
player in learning and memory processes. Surprisingly, very little information is available on how trisomy of
HSA21 alters the development and functions of microglia and what roles microglia play in the abnormal brain
development and cognitive deficits in DS. In addition, mounting evidence indicates that rodent microglia are not
able to fully mirror the properties of human microglia in normal and disease conditions. In this study, we will use
our recently created hiPSC microglial chimeric mouse model to unravel the role of microglia in DS pathogenesis
in an in vivo system with intact neural networks. We hypothesize that unlike engrafted normal human microglia,
engrafted diseased DS human microglia will show abnormal biological properties and functions, such as synaptic
pruning function in vivo. These abnormal properties of DS microglia will result in their negative regulation of the
synaptic activity and plasticity of the hippocampal neural network, critically contributing to the cognitive deficits
seen in DS. This hypothesis will be tested in three specific aims. Aim 1: we will determine the differences between
DS and control hiPSC-derived microglia in vivo in human microglial chimeric mouse brains. Aim 2: Using the
microglial chimeric mouse model, we will further examine the impact of integration of DS microglia on synaptic
plasticity of the hippocampus and learning and memory behavior of the animals. Aim 3: We will normalize the
expression of the HSA21 genes by CRISPR/Cas9 to examine how this will alter the properties of DS microglia.
Moreover, single-cell RNA-sequencing analysis of hiPSC microglial chimeric mouse brains will be performed to
compare gene expression profiles of control and DS microglia. Findings from our study using a powerful, new
hiPSC microglial chimeric mouse model will provide novel insights into the pathological roles of human microglia
in DS. Identifying the potential molecules that can be targeted to improve microglial function may provide a new
therapeutic avenue for the treatment of DS.
Terms: <Affect><Ammon Horn><Animal Behavior><Animals><Autoregulation><Behavior><Behavioral><Biological><Body Tissues><Brain><Brain Nervous System><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Candidate Disease Gene><Candidate Gene><Cas nuclease technology><Cell Body><Cells><Chimera><Chimera organism><Chromosome 21><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 deficits><Cornu Ammonis><Development><Disease><Disorder><Down's Syndrome><Encephalon><Engraftment><Environment><Exhibits><Expression Signature><Gene Expression Profile><Gene Transcription><Generations><Genes><Genetic><Genetic Transcription><Hippocampus><Homeostasis><Hortega cell><Human><Human Chromosomes><IFN><IFNAR><IFNAR1><IFNAR1 gene><Immune><Immunes><Impairment><In Vitro><Individual><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Interferons><Langdon Down syndrome><Learning><Link><Macrophage><Maintenance><Memory><Mice><Mice Mammals><Microglia><Mind><Modeling><Modern Man><Molecular><Mongolism><Murine><Mus><Mφ><Nerve Cells><Nerve Unit><Neural Cell><Neural Stem Cell><Neurocyte><Neurons><Organoids><Ortholog><Orthologous Gene><Pathogenesis><Pathogenicity><Pathologic><Pathology><Performance><Phenotype><Physiological Homeostasis><Play><Progenitor Cells><Property><RNA Expression><Regulation><Research><Rodent><Rodentia><Rodents Mammals><Role><Specific qualifier value><Specified><Synapses><Synaptic><Synaptic plasticity><System><Technology><Testing><Tissues><Transcription><Transgenic Mice><Trisomy><Trisomy 21><biologic><brain abnormalities><brain cell><brain tissue><cell type><chimeras><chromosome 21 trisomy syndrome><cognitive defects><compare to control><comparison control><congenital acromicria syndrome><developmental><developmental disease><developmental disorder><disease phenotype><dosage><gene expression pattern><gene expression signature><gitter cell><glial cell development><glial development><global gene expression><global transcription profile><hiPSC><hippocampal><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS><iPSC><iPSC technology><iPSCs><improved><in vitro Model><in vivo><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cell technology><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><inducible pluripotent stem cell><insight><intellectual and developmental disability><limited intellectual functioning><memory process><memory processing><mesoglia><microglial cell><microgliocyte><morbus Down><mouse model><murine model><nerve stem cell><neural circuit><neural circuitry><neural network><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neurocircuitry><neuron progenitors><neuronal><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuroprogenitor><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><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><perivascular glial cell><pseudohypertrophic progressive muscular dystrophy><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem cells><synapse><synapse function><synaptic circuit><synaptic circuitry><synaptic function><synaptic pruning><tool><transcriptional profile><transcriptional signature><transcriptome><trisomy 21 syndrome>