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Principal Investigator: Janine M LaSalle
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2024
Award: $670,005
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
The human fetal brain consumes up to 60% of the body’s oxygen and energy consumption,
despite making up ~13% of body mass. When the demand for oxygen in the placenta and
developing brain exceeds its supply, hypoxia is induced, followed by changes to mitochondrial
respiration, protein translation, and oxidative stress. Oxidative stress and epigenetic mechanisms
within the placental-brain axis act at the interface of genetic and environmental risk factors in
autism spectrum disorders. Using placental samples from a prospective high-risk cohort, we
recently identified and named a novel gene NHIP (neuronal hypoxia inducible, placenta
associated) and demonstrated its epigenetic, genetic, and transcriptional association with autism.
NHIP is transiently expressed in response to hypoxia and neuronal differentiation, two examples
of elevated oxidative stress. NHIP encodes a previously undiscovered micropeptide that localizes
to the nucleus and is predicted to be neuroprotective, based on the lower expression of NHIP in
placenta and brain samples from autism compared to control. The predicted structure of the NHIP
peptide is an amphipathic helix that has similarity to a 9aaTAD motif found in transcriptional
activation domains of many DNA binding proteins. We propose to test the hypothesis that NHIP
acts as a competitive inhibitor of multi-protein complexes, thereby protecting developing and
differentiating neurons following transient waves of hypoxia. Because NHIP is an “undiscovered
protein” whose function had not been described before our recent study, this proposal will focus
on the major research questions that are critical for determining the therapeutic relevance of
NHIP. Specifically, what is the function of NHIP in neurons and brain, how is it regulated in
response to hypoxia, and is it protective of neuronal oxidative stress? We propose three specific
aims using well-characterized in vitro and in vivo models, including an inducible human neuronal
cell line (LUHMES) engineered for NHIP transcript or peptide loss, human brain extracts with
known NHIP genotype and expression levels, and mouse brain following NHIP peptide
administration and/or hypoxia. Aim 1 will determine the molecular mechanisms of NHIP function
and examine both protein-specific and global cellular impacts of NHIP loss. Aim 2 will determine
how NHIP is transcriptionally responsive to hypoxia-induced oxidative stress by identifying the
transcription factors and their genetic and epigenetic requirements for binding to the NHIP
promoter and enhancer. Aim 3 will determine if exogenously delivered NHIP/NHIP protects
neurons and embryonic neural precursor cells from hypoxia-induced oxidative stress. Together,
the results from these proposed studies will provide the first functional characterization of NHIP,
an understudied micropeptide that is associated with resilience to autism spectrum disorders. The
potential impact of these results will be a potential therapeutic small molecule that could be used
in early intervention therapy for autism and other neurodevelopmental or hypoxia-related
disorders.
Terms: <21+ years old><22q13><ASD><Adult><Adult Human><Affinity><Amino Acids><Animal Model><Animal Models and Related Studies><Antioxidants><Assay><Autism><Autism Diagnosis><Autistic Disorder><Autopsy><Back><Basal Transcription Factor><Basal transcription factor genes><Binding><Binding Proteins><Bioassay><Biological Assay><Birth><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><Cas nuclease technology><Causality><Cell Anoxia><Cell Body><Cell Function><Cell Hypoxia><Cell Line><Cell Nucleus><Cell Physiology><Cell Process><CellLine><Cells><Cells Placenta-Tissue><Cellular Anoxia><Cellular Function><Cellular Hypoxia><Cellular Physiology><Cellular Process><Cerebroatrophic Hyperammonemia><ChIP assay><Chromatin><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><Complex><Consumption><DNA Methylation><DNA-Binding Proteins><Data><Depakote><Depakote ER><Disease><Disorder><Distal><Divalproex><Dorsum><EWAS><Early Infantile Autism><Early Intervention><Embryo><Embryonic><Encapsulated><Encephalon><Energy consumption><Engineering><Enhancers><Environmental Factor><Environmental Risk Factor><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Etiology><Folic Acid Deficiency><Future><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Risk><Genetic Transcription><Genetic predisposing factor><Genomics><Genotype><Gestation><Goals><Human><Hypoxia><Hypoxic><In Vitro><Infantile Autism><Intermediary Metabolism><Kanner's Syndrome><Ligand Binding Protein><Ligand Binding Protein Gene><Macromolecular Protein Complexes><Maps><MeCP-2 protein><MeCP2><MeCP2 protein><Messenger RNA><Metabolic Processes><Metabolism><Methyl CpG Binding Protein 2><Methyl CpG binding protein MeCP2><Methyl-CpG binding protein 2><Methyl-CpG-Binding Protein 2><Methyl-DNA binding protein MECP2><Methylation><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Molecular><Molecular Interaction><Multiprotein Complexes><Murine><Mus><Names><Nerve Cells><Nerve Unit><Neural Cell><Neural Stem Cell><Neurocyte><Neuronal Differentiation><Neuronal Hypoxia><Neurons><Normal Placentoma><Nucleus><O element><O2 element><Oxidative Stress><Oxidative Stress Induced Gene Expression Via Nrf2><Oxidative Stress Induction><Oxidative Stress Pathway><Oxygen><Oxygen Consumption><Oxygen Deficiency><Parturition><Pathway interactions><Peptides><Phenotype><Placenta><Placenta Diseases><Placenta Disorders><Placenta Embryonic Tissue><Placental Diseases><Placentome><Pre-Clinical Model><Preclinical Models><Pregnancy><Primates><Primates Mammals><Property><Protein Binding><Proteins><Proteomics><Publishing><RNA Expression><RNA Processing><RNA Splicing><Regulation><Reporter><Research><Respiration><Response Elements><Rett Disorder><Rett Syndrome><Risk-associated variant><Sampling><Splicing><Strains Cell Lines><Structure><Subcellular Process><Synapses><Synaptic><Testing><Therapeutic><Therapeutic Intervention><Transactivation><Transcript><Transcription><Transcription Activator><Transcription Coactivator><Transcription Factor Coactivator><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Activation Domain><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Translating><Translations><Valproic Acid><adulthood><aminoacid><autism model><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><bound protein><causation><chromatin immunoprecipitation><cohort><compare to control><comparison control><cultured cell line><disease causation><disease risk><disorder risk><environmental risk><epigenetically><epigenome><epigenome wide association analysis><epigenome-wide association studies><fetal><folate deficiency><gene locus><genetic locus><genetic risk factor><genomic location><genomic locus><high risk><human fetal brain><human model><in utero><in vivo><in vivo Model><inherited factor><inhibitor><intervention therapy><lipid based nanoparticle><lipid nanoparticle><mRNA><maternal adiposity><maternal obesity><mitochondrial><model of animal><model of autism spectrum disorder><model of human><mouse model><murine model><name><named><naming><nano particle delivery><nanoparticle delivered><nanoparticle delivery><necropsy><nerve stem cell><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neurogenesis><neuron progenitors><neuronal><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuroprogenitor><neuroprotection><neuroprotective><novel><overexpress><overexpression><pathway><placental disorders><polygenic risk score><postmortem><promoter><promotor><prospective><protein complex><protein protein interaction><resilience><resilient><respiratory mechanism><response><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><small molecule therapeutics><synapse><traffic-related air pollution><trans-activation><transcription co-activator><transcription factor><transcriptional co-activator><translation>