Prenatal Origins of Neurometabolic Consequences

神经代谢后果的产前起源

• 批准号: 10684885
• 负责人: Sherin U Devaskar
• 金额: $ 63.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684885
• 关键词: Adult; Adult Children; Affect; Alzheimer' s Disease; Anxiety; Asphyxia Neonatorum; Attention deficit hyperactivity disorder; Behavioral; Bioinformatics; Biological Process; Brain; Brain Hypoxia-Ischemia; CRISPR/Cas technology; Caloric Restriction; Cell Count; Cells; Central Nervous System; Cerebral cortex; Child; Clinical; Copy Number Polymorphism; Cortical Dysplasia; DNA Sequence Alteration; Dementia; Dependence; Detection; Development; Developmental Delay Disorders; Diagnostic; Dietary Intervention; Early Intervention; Embryo; Environment; Exposure to; Failure; Fetal Growth Retardation; Fetus; Gene Deletion; Gene Mutation; Genes; Genetic Transcription; Genomics; Germ Lines; Gliosis; Glucose; Glucose Transporter; Goals; Health; Heterozygote; Human; Huntington Disease; Hyperactivity; Hypoglycemia; Hypoxia; In Situ Hybridization; Incidence; Infant; Injury; Intervention; Investigation; Ischemia; Ketones; Life Cycle Stages; Link; Malignant Neoplasms; Meningomyelocele; Mus; Mutation; Nerve Degeneration; Neurodevelopmental Disorder; Neurons; Non-Invasive Detection; Organoids; Phenotype; Placenta Diseases; Plasma; Process; Protein Isoforms; Proteins; Reporting; Rodent; SLC2A1 gene; Seizures; Senile Plaques; Societies; Synapses; Syndrome; Testing; Translating; Vesicle; autism spectrum disorder; cell type; chromosome 22q deletion syndrome; cognitive disability; diagnostic value; dietary; early screening; endophenotype; excitatory neuron; exome; extracellular; extracellular vesicles; fetal; gene environment interaction; genome sequencing; glucose transport; induced pluripotent stem cell; infant outcome; insight; intrauterine environment; ketogenic diet; ketogentic; metabolomics; migration; nerve stem cell; nestin protein; neural; neurobehavior; neurobehavioral; neurodevelopment; neurogenesis; neuromechanism; novel; offspring; overexpression; postnatal; pre-clinical assessment; premature; prenatal; prognostication; single-cell RNA sequencing; transcriptome; transcriptome sequencing; transcriptomics; whole genome

1 ABSTRACT 2 3 There is growing incidence of neurodevelopmental disorders (NDD). Causes for NDDs include ischemic 4 placental disorders (IPD) with fetal/intra-uterine growth restriction (FGR/IUGR), perinatal asphyxia, and 5 hypoglycemia. Exploration of connections between aberrant placental health and NDDs has occurred. Besides 6 the intra-uterine environment (IUE), genetic mutations also contribute to a subset of NDDs, forming an IUE-gene 7 paradigm. We have focused on the neuronal glucose transporter isoform 3 (GLUT3; gene: glut3). Glut3 gene 8 mutations are reported with NDDs/cognitive disabilities. Glut3 mutations with exposure to an adverse IUE may 9 portray expansive effects upon NDD endophenotypes. Development of diagnostics and early dietary 10 interventions is much needed. We have shown that IUGR and hypoxia-ischemia perturb developing brain glut3 11 expression perturbing neurobehavior. We also created murine glut3 deletions, that reduced trans-placental 12 glucose transport leading to postnatal NDD (excitatory autism spectrum disorders), where small extracellular 13 vesicles (sEVs) fueling diagnostics, and ketogenic dietary intervention are being explored. We next disengaged 14 placental glut3 gene from neural-specific glut3 mutations towards deciphering independent neural mechanisms 15 behind NDDs. We also created glut3 expressing human brain organoids from induced pluripotent stem cells 16 (iPSCs). Assessing pre-clinical ketogenic dietary effects targeting NDDs, will yield novel results. To achieve this 17 goal, we will test the hypothesis, that IUE and neural glut3 mutations/dependency cause NDDs by 18 perturbing neurodevelopment with a potential for amelioration. The aims are: 1) a. To investigate changes 19 in cell numbers per cell type and cell-specific transcriptomics in cerebral cortices (CC) with neural progenitor 20 cellular (NPC) absence of glut3 by using nestin-driven conditional null postnatal mice. This will be accomplished 21 by 10X genomics single cell (sc) RNA-sequencing and bioinformatic analyses, followed by in-situ hybridization 22 (ISH)/immunohistochemical (IHC) detection of major changes in key transcribed/translated products in specific 23 cell types. b. To assess administration of prenatal versus postnatal ketogenic diet as an early intervention in 24 ameliorating NDD. 2) a. To explore neural processes and cellular profile in CC with or without MoMCR/IUGR in 25 targeted absence or overexpression (OE) of glut3 in excitatory neurons/NPCs using Emx1-driven conditional 26 null and OE mice during the life course from embryonic and postnatal to the adult. This will entail deconvoluting 27 bulk CC RNA-seq with ISH/IHC, with non-invasive detection of perturbed transcriptome/proteins in circulating 28 sEVs. b. To examine the impact on CSF/plasma metabolomics, neuronal function and neurobehavior in the adult 29 offspring. 3) a. To develop cortical organoids from control iPSCs with glut3 OE and/or glut3 deletions, and 30 examine cellular profiles by deconvoluting organoid RNA-seq with scRNA-seq and ISH/IHC. b. To interrogate 31 the effect of hypoxia and hypoglycemia with/without ketones/lactate on iPSCs, NPCs and cortical organoids.

1)抽象

项目成果

Murine maternal dietary restriction affects neural Humanin expression and cellular profile.

鼠产妇饮食限制会影响神经人类的表达和细胞谱。

• DOI: 10.1002/jnr.24568
• 发表时间: 2020-05
• 期刊: Journal of neuroscience research
• 影响因子: 4.2
• 作者: Baldauf C;Sondhi M;Shin BC;Ko YE;Ye X;Lee KW;Devaskar SU
• 通讯作者: Devaskar SU

Early life high-fat diet exposure maintains glucose tolerance and insulin sensitivity with a fatty liver and small brain size in the adult offspring.

生命早期的高脂肪饮食暴露可维持成年后代的葡萄糖耐量和胰岛素敏感性，并导致脂肪肝和较小的大脑尺寸。

• DOI: 10.1016/j.nutres.2019.08.004
• 发表时间: 2019
• 期刊: Nutrition research (New York, N.Y.)
• 作者: Shin,Bo-Chul;Ghosh,Shubhamoy;Dai,Yun;Byun,ShinYun;Calkins,KaraL;Devaskar,SherinU
• 通讯作者: Devaskar,SherinU

Humanin (HN) and glucose transporter 8 (GLUT8) in pregnancies complicated by intrauterine growth restriction.

• DOI: 10.1371/journal.pone.0193583
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Janzen C;Lei MYY;Jeong ISD;Ganguly A;Sullivan P;Paharkova V;Capodanno G;Nakamura H;Perry A;Shin BC;Lee KW;Devaskar SU
• 通讯作者: Devaskar SU

Developing Brain Glucose Transporters, Serotonin, Serotonin Transporter, and Oxytocin Receptor Expression in Response to Early-Life Hypocaloric and Hypercaloric Dietary, and Air Pollutant Exposures.

脑葡萄糖转运蛋白，5-羟色胺，5-羟色胺转运蛋白和催产素受体的表达，响应早期生命的低温和过度饮食以及空气污染物的暴露。

• DOI: 10.1159/000514709
• 发表时间: 2021
• 期刊: Developmental neuroscience
• 影响因子: 2.9
• 作者: Ye X;Shin BC;Baldauf C;Ganguly A;Ghosh S;Devaskar SU
• 通讯作者: Devaskar SU

Adult glut3 homozygous null mice survive to demonstrate neural excitability and altered neurobehavioral responses reminiscent of neurodevelopmental disorders.

• DOI: 10.1016/j.expneurol.2021.113603
• 发表时间: 2021-04
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Shin BC;Cepeda C;Eghbali M;Byun SY;Levine MS;Devaskar SU
• 通讯作者: Devaskar SU