Prenatal Origins of Neurometabolic Consequences

神经代谢后果的产前起源

• 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
• 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' 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

 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（由申请人提供）： 儿童发育迟缓的发生率占美国人口的 18%，其中男孩多于女孩 环境因素（例如胎儿生长偏差和低血糖）和遗传畸变是发育迟缓和自闭症谱系障碍的病因。 (ASD) 与 12 号染色体上的拷贝数变异 (CNV)、Slc2A3 基因的缺失或重复有关。ASD 是终生的与大脑突触断开相关的神经发育障碍 (NDD)，Glut3 蛋白是神经元促进性葡萄糖转运蛋白，可促进神经细胞增殖和分化、突触形成/可塑性和功能/神经传递所需的氧化代谢。随着更新的基因技术的出现，我们之前在经典的单等位基因中观察到了与 CNV 相关的现象。 Slc2A3 缺失小鼠胎儿生长受限 (FGR)，雄性表现出自闭症谱系障碍 (ASD) 症状 为了区分 FGR 对异常脑器官发生和发病的影响，我们发现大脑皮层和海马神经元中 Glut3 的缺乏将揭示以下范围的表型。为检验这一假设，我们提出以下具体建议。旨在通过破坏条件性神经元 glut3 缺失小鼠系 (glut3loxP/loxP/nestinCre+) 中的神经元特异性 Slc2A3，研究对以下方面的影响： 1. a. 不同妊娠阶段（G13、G19）的胎盘和胎儿大脑 Slc2A3 表达和功能) 和 b. 胎儿生长受限 (FGR) 对胎盘和胎儿大脑 Slc2A3 表达和功能的作用 2. 出生后。 a. 代谢状态，包括血浆、脑脊液和大脑（神经元和神经胶质）代谢特征，以及补偿机制，b. 检测不同细胞类型和过程异常。包括活动、癫痫发作、认知、工作记忆、焦虑、社交、发声和刻板印象，以及膜片钳神经元的电生理学以检测功能障碍，以及我们提出的研究结果将告诉我们 glut3 缺乏对 ASD 的贡献和影响，为未来检测多因素 ASD/NDD 中 glut3 基因变异的人类研究奠定基础。所获得的见解将可推广到预防和治疗早期发育过程中遇到的与神经元葡萄糖供应不足（例如 FGR）相关的其他病症，并导致具有以下临床特征的 NDD。自闭症谱系障碍（ASD），有时表现为脑电图癫痫发作和婴儿小头畸形。