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.

人胎儿的大脑消耗了全身高达60%的氧气和能量消耗，尽管占体重的 13%，但胎盘对氧气的需求量却很大。发育中的大脑超出其供应，引起缺氧，随后线粒体发生变化呼吸、蛋白质翻译和氧化应激和表观遗传机制。在胎盘-大脑轴内，在遗传和环境风险因素的界面上发挥作用使用来自前瞻性高风险队列的胎盘样本，我们最近发现并命名了一个新基因NHIP（神经元缺氧诱导，胎盘相关）并证明了其与自闭症的表观遗传、遗传和转录关联。 NHIP 在缺氧和神经元分化反应中短暂表达，两个例子 NHIP 编码一种先前未发现的定位微肽。基于 NHIP 在细胞核中的较低表达，预计具有神经保护作用自闭症患者的胎盘和大脑样本与对照组的预测结构相比。肽是一种两亲性螺旋，与转录中发现的 9aaTAD 基序相似我们建议检验 NHIP 的假设。作为多蛋白复合物的竞争性抑制剂，从而保护发育和因为 NHIP 是一种“未被发现的”机制。在我们最近的研究之前，其功能尚未被描述过，该提案将重点关注对确定治疗相关性至关重要的主要研究问题具体来说，NHIP在神经元和大脑中的功能是什么，它是如何被调节的。对缺氧的反应，它对神经元氧化应激有保护作用吗？我们提出了三种具体的方案？目标是使用特征良好的体外和体内模型，包括可诱导的人类神经元细胞系（LUHMES）针对 NHIP 转录物或肽丢失而设计，人脑提取物已知 NHIP 基因型和表达水平，以及小鼠大脑追踪 NHIP 肽目标 1 将确定 NHIP 功能的分子机制。并检查 NHIP 损失的蛋白质特异性和整体细胞影响将确定。 NHIP 如何通过识别对缺氧诱导的氧化应激进行转录反应转录因子及其与 NHIP 结合的遗传和表观遗传要求目标 3 将确定外源传递的 NHIP/NHIP 是否具有保护作用。神经元和胚胎神经前体细胞共同应对缺氧引起的氧化应激。这些拟议研究的结果将提供 NHIP 的第一个功能特征，一种尚未被研究的微肽，与自闭症谱系障碍的恢复能力有关。这些结果的潜在影响将是一种可以使用的潜在治疗小分子用于自闭症和其他神经发育或缺氧相关的早期干预治疗失调。