Gag-like Proteins in exosome-mediated Neural Development and Fetal Alcohol Spectrum Disorders

外泌体介导的神经发育和胎儿酒精谱系障碍中的堵嘴样蛋白

• 批准号: 10224820
• 负责人: Marisa Pinson
• 金额: $ 3.47万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224820
• 关键词: Affect; Alcohol abuse; Alcoholism; Alcohols; Angelman Syndrome; Base of the Brain; Biological Assay; Brain; CRISPR/Cas technology; Capsid; Cell Death; Cell Lineage; Cells; Child; Cognitive deficits; Collection; DNA; Data; Development; Developmental Disabilities; Disease; Early Intervention; Endogenous Retroviruses; Enterobacteria phage P1 Cre recombinase; Ethanol; Family; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; Gene Transfer; Genomics; Goals; Growth; Immunoprecipitation; Infection; Institutes; Intervention; Lead; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Membrane; Messenger RNA; Mission; Modeling; Molecular Chaperones; Neurodevelopmental Disorder; Neurons; Nuclear; Organism; Outcome; Prevention; Protein Overexpression; Proteins; RNA; Research; Research Training; Role; School-Age Population; Scientist; Second Pregnancy Trimester; Testing; Therapeutic; Third Pregnancy Trimester; Time; Training; Transcriptional Regulation; Transfer RNA; Ultrasonography; alcohol effect; alcohol exposure; alcohol related problem; base; career; disability; embryonic stem cell; exosome; extracellular; fetal; in vivo; intercellular communication; loss of function; migration; nerve stem cell; neuroadaptation; neurodevelopment; neurogenesis; neuromechanism; neuroregulation; non-genetic; novel; overexpression; pediatrician; pregnant; prevent; protein expression; protein function; protein protein interaction; relating to nervous system; self-renewal; social culture; stem cell division; stem cell proliferation

Project Summary Prenatal alcohol exposure (PAE) can result in a collection of brain-based disabilities termed Fetal Alcohol Spectrum Disorders (FASD). FASDs are estimated to affect ~1-5% of school-aged children in the US. While sociocultural factors make PAE difficult to prevent, FASD may be prevented by early interventions. The proposed studies, aimed at identifying novel, alcohol-sensitive brain growth control mechanisms mediated by a family of Gag-Like Proteins (GLPs), may uncover new ways to minimize effects of PAE. GLPs are genomic remnants of ancient retroviral infections that have since been adapted for utilization in the host organism. Some have evolved to control transcriptional regulatory networks in embryonic stem cells, whereas others like Arc facilitate plasticity in differentiated neurons, and have been hypothesized to mediate some cognitive deficits observed in neurodevelopmental disorders like Angelman’s syndrome. Arc has also recently been identified as a capsid forming protein capable of transporting its own mRNA in exosomes between neural cells, reminiscent of its Gag origin. Other GLPs may also retain functional aspects of Gag, such as the ability to interact with mRNAs and to self-target for membrane bound export. These data raise the exciting possibility that GLPs may facilitate intercellular transfer of RNAs and therefore serve as a means for programming the development and maturation of neural stem cell ensembles. Preliminary data indicate that expression of two GLPs (PEG10 and PNMA2) are selectively induced in fetal neural stem cells, following alcohol exposure. The overarching hypotheses are that these GLPs, through both intracellular mechanisms and exosome-mediated intercellular communication, control neural stem cell renewal and facilitate neurogenesis, and that perturbations in GLP expression due to alcohol exposure will result in loss of stem cell renewal and diminished neurogenesis. The immediate goal will be to identify RNA and protein partners of GLPs PEG10 and PNMA2 which mediate ethanol-effects on neural differentiation and development. Aim 1: Determine the intracellular role of Gag-like proteins PEG10 and PNMA2 in the basal and ethanol influenced differentiation of neural stem cells and neural development. Aim 2: Determine the extracellular role of PEG10 and other Gag-like proteins present in exosomes in intercellular communication and coordination of neural development under basal and ethanol conditions. Aim 3: Determine the in vivo interaction between Gag-like proteins and PAE on fetal neural development. These studies are expected to uncover novel GLP mediators of differentiation that may be manipulated in exosomes to control self-renewal and maturation of neural stem cell ensembles and to minimize effects of PAE on early neural development. This training plan’s focus on disrupting the connection between PAE and FASD integrates well with a career goal to become a pediatrician-scientist with a focus on developmental disabilities.

项目摘要 产前酒精暴露（PAE）可能导致一系列称为胎儿酒精的脑部疾病 频谱障碍（FASD）。据估计，FASD会影响美国约1-5％的学龄儿童。尽管 社会文化因素使PAE难以预防，FASD可以通过早期干预来预防。提议 研究旨在识别由一家家族介导的新型，对酒精敏感的大脑生长控制机制 GAG样蛋白（GLP）可能会发现最小化PAE影响的新方法。 GLP是古代逆转录病毒感染的基因组残留物，此后已适应用于利用 宿主有机体。一些已经进化为控制胚胎干细胞中的转录调节网络， 而其他人则在差异化神经元中喜欢弧形最喜欢的可塑性，并被认为是介导的 在神经发育障碍中观察到的一些认知缺陷，例如安吉尔曼综合症。弧也有 最近被鉴定为一种可以在外泌体中运输其自身mRNA的衣壳形成的蛋白 神经细胞，让人联想起其插科打的起源。其他GLP也可能保留GAG的功能方面，例如 能够与mRNA相互作用和自动靶向以进行膜结合的出口。这些数据引起了令人兴奋的 GLP可以促进RNA的细胞间转移的可能性，因此是一种手段 编程神经干细胞组合的发展和成熟。 初步数据，表明在胎儿中选择性诱导了两个GLP（PEG10和PNMA2）的表达 酒精暴露后神经干细胞。总体假设是这些GLP，通过两者 细胞内机制和外泌体介导的细胞间通信，控制神经元干细胞更新 并促进神经发生，并且由于酒精暴露而引起的GLP表达扰动将导致损失 干细胞更新并减少神经发生。直接目标是识别RNA和蛋白质 GLPS PEG10和PNMA2的合作伙伴介导乙醇对神经元分化和发育的影响。 目标1：确定基底和乙醇中GAG样蛋白PEG10和PNMA2的细胞内作用 影响神经元干细胞和神经元发育的分化。 AIM 2：确定PEG10和其他GAG样蛋白的细胞外作用 基本和乙醇条件下神经发育的沟通和协调。 AIM 3：确定胎儿神经发育中GAG样蛋白与PAE之间的体内相互作用。 预计这些研究将发现可能在 控制神经干细胞集合的自我更新和成熟的外泌体，并最大程度地减少PAE的影响 关于早期神经发育。该培训计划的重点是破坏PAE与FASD之间的联系 与职业目标融为一体，成为一名专注于发育障碍的儿科医生。