Prenatal Origins of Neurometabolic Consequences

神经代谢后果的产前起源

基本信息

批准号：
9029338
负责人：
Sherin U Devaskar
金额：
$ 31.64万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029338
关键词：
Adult Age Alzheimer&apos s Disease Anxiety Apoptosis Asphyxia Neonatorum Assimilations Attention deficit hyperactivity disorder Autistic Disorder Behavior Biological Models Brain Caloric Restriction Cell Differentiation process Cell Proliferation Cell Respiration Cerebrospinal Fluid Cerebrum Child Chromosomes, Human, Pair 12 Clinical Cognition Cognitive Comorbidity Copy Number Polymorphism Development Developmental Delay Disorders Diabetes Mellitus Dietary Intervention Disease Electrophysiology (science)Embryo Environmental Risk Factor Face Family Family dynamics Fetal Growth Fetal Growth Retardation Future GLUT-3 protein Genes Genetic Glucose Glucose Transporter Growth Head Health Hippocampus (Brain)Human Hypoglycemia Immunohistochemistry Impairment Incidence Individual Infection Inflammation Intellectual functioning disability Intervention Ketones Life Metabolic Microcephaly Mono-S Morbidity - disease rate Morphology Mus Nerve Degeneration Neurodevelopmental Disorder Neuroglia Neurons Nutrient Organogenesis Paternal Age Pharmaceutical Preparations Phenotype Plasma Play Population Pregnancy Process Productivity Protein Isoforms Proteins Rett Syndrome Role SLC2A1 gene Seizures Short-Term Memory Socialization Staging Stress Symptoms Synapses Syndrome Testing Therapeutic Therapeutic Intervention Time Translations Uterus Variant Zebrafish autism spectrum disorder boys brain cell brain morphology cell type endophenotype fetal functional disability genetic technology girls glucose transport glucose uptake infancy insight ketogenic diet male maternal diabetes metabolic profile migration nervous system disorder neurobehavioral neurogenesis neuropsychological neurotransmission patch clamp postnatal premature prenatal prevent response screening small molecule synaptogenesis vocalization

项目摘要

DESCRIPTION (provided by applicant): The incidence of developmental delays in children is 18% of the US population, with boys outnumbering girls. Environmental factors (e.g. fetal growth deviations and hypoglycemia) and genetic aberrations play etiological roles. Developmental delays and autism spectrum disorders (ASDs) have been associated with copy number variations (CNVs), deletion or duplication of the Slc2A3 gene on chromosome 12. ASDs are life-long neurodevelopmental disorders (NDD) with brain synaptic disconnectivity. Slc2A3 gene translation product, Glut3 protein is the neuronal facilitative glucose transporter that fuels oxidative metabolism necessary for neural cell proliferation and differentiation, synaptic formation/plasticity and function/neurotransmission. The phenotypically distinct human GLUT3 deficiency associated with CNVs is being described in children with the advent of newer genetic technologies. We previously observed that in the classical mono-allelic Slc2A3 deletion mouse with fetal growth restriction (FGR), males expressed ASD symptoms. To separate the impact of FGR on aberrant brain organogenesis and the advent of morbidities, we hypothesize that lack of Glut3 in cerebral cortical and hippocampal neurons will reveal a phenotype ranging from autism to intellectual disability, thereby unraveling possibilities for screening and interventions, that an aid individuals with these presenting features and prevent some NDDs and their associated co-morbidities. To test this hypothesis, we propose the following specific aims by disrupting neuron-specific Slc2A3 in a conditional neuronal glut3 null deletion mouse line (glut3loxP/loxP/nestinCre+), to study the impact on: 1. a. Placental and fetal brain Slc2A3 expression and function at different gestational stages (G13, G19) and b. the role of fetal growth restriction (FGR) on placental and fetal brain Slc2A3 expression and function. 2. Postnatal a. metabolic status which includes plasma, cerebro-spinal fluid and brain (neuronal and glial) metabolic profile with compensatory mechanisms, b. brain morphology and immunohistochemistry to detect different cell types and aberrations in processes. 3. Postnatal and adult a. neurobehavioral phenotype including activity, seizures, cognition, working memory, anxiety, socialization, vocalization and stereotypies, with b. electrophysiology in patch-clamped neurons to detect functional impairments, and possibility of reversal with a ketogenic diet. The results of our proposed studies will inform us about the contribution and impact of glut3 deficiency on ASDs, setting the stage for future endophenotype human studies in detecting glut3 gene variations in the multifactorial ASD/NDDs. This will enable subsequent therapeutic discovery. The insights gained will be generalizable in preventing and treating other conditions related to deficient neuronal glucose supply (e.g. FGR) encountered during early development and resulting in NDDs with clinical features of ASDs, sometimes presenting with EEG seizures and infantile microcephaly.

描述（由应用程序提供）：儿童发育延迟的事件是美国人口的18％，男孩外部人数女孩。环境因素（例如胎儿生长出发和低血糖症）和遗传畸变起病因的作用。发育延迟和自闭症谱系障碍（ASDS）与第12染色体上的SLC2A3基因的拷贝数变化（CNV），删除或重复相关。ASDS是终身神经发育障碍（NDD），具有脑综合性脱节性。 SLC2A3基因翻译产物GLUT3蛋白是神经元友好的葡萄糖转运蛋白，它为神经元细胞增殖和分化，突触形成/可塑性和功能/神经传递所必需的氧化代谢提供。在较新的遗传技术出现的儿童中，描述了与CNV相关的表面截然不同的人Glut3缺乏症。我们先前观察到，在经典的单相关SLC2A3缺失小鼠具有胎儿生长限制（FGR）的小鼠中，男性表达了ASD症状。为了区分FGR对异常脑器官发生的影响和病态的冒险，我们假设在脑皮质和海马神经元中缺乏GLUT3将揭示出一种表型，从自闭症到智力残疾，从而揭示了筛查和干预措施的可能性，以帮助他们与这些群体相关联，并将某些人与某些人相关联。为了检验这一假设，我们通过在条件神经元GLUT3 NULL缺失小鼠系（Glut3loxp/loxp/loxp/nestincre+）中破坏神经特异性SLC2A3来提出以下特定目标，以研究：1。a。胎盘和胎儿脑SLC2A3表达和功能在不同的妊娠期（G13，G19）和b。胎儿生长限制（FGR）在斑点和胎儿脑SLC2A3表达和功能上的作用。 2。产后a。代谢状态，包括血浆，脑脊髓液和脑（神经元和神经胶质）代谢特征，并具有补偿机制，b。脑形态和免疫组织化学，以检测过程中的不同细胞类型和畸变。 3。产后和成人a。神经行为表型，包括活动，癫痫发作，认知，工作记忆，动画，社交，发声和刻板印象，以及b。斑块钳神经元中的电生理学检测功能障碍，并可能通过生酮饮食逆转。我们提出的研究的结果将为我们告知GLUT3缺乏对ASD的贡献和影响，为未来的内表型人类研究奠定了阶段，以检测多因素ASD/NDDS中的GLUT3基因变异。这将使随后的治疗发现。获得的见解将在预防和治疗与早期发育过程中遇到的与确定的神经元葡萄糖供应（例如FGR）有关的其他疾病方面具有普遍性，并导致具有ASDS临床特征的NDD，有时会出现EEG癫痫发作和婴儿小头骨。