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Placental identified NHIP regulating neuronal oxidative stress in autism

胎盘发现 NHIP 调节自闭症神经元氧化应激

基本信息

批准号：
10717990
负责人：
Janine M LaSalle
金额：
$ 66.61万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10717990
关键词：
22q13 Adult Affinity Amino Acids Animal Model Antioxidants Autism Diagnosis Autopsy Back Binding Binding Proteins Biological Assay Birth Brain CRISPR/Cas technology Cell Hypoxia Cell Line Cell Nucleus Cell physiology Cells Chromatin Complex Consumption DNA Methylation DNA-Binding Proteins Data Disease Distal Early Intervention Embryo Encapsulated Energy consumption Engineering Enhancers Environmental Risk Factor Epigenetic Process Etiology Folic Acid Deficiency Future Genes Genetic Genetic Risk Genetic Transcription Genomics Genotype Goals Human Hypoxia In Vitro Maps Messenger RNA Metabolism Methyl-CpG-Binding Protein 2 Methylation Mitochondria Modeling Molecular Multiprotein Complexes Mus Names Neuronal Differentiation Neuronal Hypoxia Neurons Oxidative Stress Oxidative Stress Induction Oxidative Stress Pathway Oxygen Oxygen Consumption Pathway interactions Peptides Phenotype Placenta Placenta Diseases Pre-Clinical Model Pregnancy Primates Property Proteins Proteomics Publishing RNA Processing RNA Splicing Regulation Reporter Research Respiration Response Elements Rett Syndrome Sampling Structure Synapses Testing Therapeutic Therapeutic Intervention Transactivation Transcript Transcription Coactivator Transcriptional Activation Domain Translating Translations Valproic Acid autism spectrum disorder chromatin immunoprecipitation cohort comparison control disorder risk epigenome epigenome-wide association studies fetal genetic risk factor genomic locus high risk human fetal brain human model in utero in vivo in vivo Model inhibitor lipid nanoparticle maternal obesity mouse model nanoparticle delivery nerve stem cell neurogenesis neuroprotection novel overexpression polygenic risk score promoter prospective protein complex protein protein interaction resilience response risk variant small molecule therapeutics traffic-related air pollution transcription factor

项目摘要

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.

胎儿的大脑消耗了人体60%的氧气和能量消耗，