Prenatal microRNA neuro-therapeutics for fetal alcohol exposure

针对胎儿酒精暴露的产前 microRNA 神经疗法

基本信息

批准号：
9240564
负责人：
Rajesh C Miranda
金额：
$ 35.17万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-10 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240564
关键词：
3&apos Untranslated Regions Address Adult Affect Agonist Alcohol consumption Alcohols Anatomy Binding Biological Birth Brain Brain Injuries Cell Count Cell Maturation Cell Transplants Cells Cessation of life Data Daughter Development Economic Burden Education Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Ethanol Exposure to Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetal Therapies Fetus Genetic Genetic Crosses Genetic Models Goals Growth Health Injury Intervention Link Mediating Messenger RNA MicroRNAs Modeling Molecular Mus NFIA gene Neurodevelopmental Disability Neuronal Differentiation Neurons Nicotine Nicotinic Receptors Outcome Outcome Study Pattern Pharmacology Phase Pregnancy Prenatal care Prevalence Public Health Publishing Receptor Activation Reporter Reporting Residual state Risk Role Signal Pathway Signal Transduction Stem cells Technology Teratogens Testing Therapeutic Therapeutic Intervention Tissues Translations Ultrasonography Untranslated RNA Viral Woman alcohol effect alcohol exposure base cellular targeting drinking fetal improved in utero innovation nerve stem cell neurodevelopment neurogenesis non-genetic novel novel strategies overexpression preclinical study premature prenatal prenatal therapy prevent programs public health relevance repaired self-renewal socioeconomics stem cell division transcription factor unintended pregnancy varenicline

项目摘要

DESCRIPTION (provided by applicant): Maternal alcohol consumption during early pregnancy is difficult to prevent due to the prevalence of both unplanned pregnancies and binge patterns of alcohol consumption in the US. Exposure is common during the 1st trimester, when neural stem cells (NSCs) begin producing neurons, increasing the risk for neurodevelopmental disability. There is a critical, un-met need for biomedical interventions to mitigate effects of alcohol exposure. A lack of such interventions means that we can do little to help women who subsequently seek prenatal care for fetal alcohol exposure. Our long-term goal is to find ways to mitigate brain damage due to teratogens like ethanol. Our approach to reversing ethanol's effects focuses on intervening prenatally to manipulate the growth potential of residual fetal NSCs. This approach is based on our key findings that ethanol does not kill NSCs, but promotes premature maturation. A class of small regulatory RNAs, miRNAs, mediates many of these ethanol effects. Ethanol deregulates miRNA (miR153, miR335) control of differentiation-promoting transcription factors (ndTFs) like Nfia and Nfib and NeuroD1, resulting in premature ndTF expression in NSCs. Moreover, nicotinic acetylcholine receptor (nAChR) agonists can prevent and even reverse effects of ethanol on miRNAs and their target ndTFs. Collectively, these data support two hypotheses: (1) ethanol depletes NSCs by interfering with miRNA-ndTF networks that prevent premature NSC maturation, and (2) both miRNAs and nAChR agonists prevent and perhaps even reverse effects of fetal ethanol exposure. Aim 1 will identify key ndTFs that facilitate ethanol effects on NSC self-renewal and maturation while Aim 2 will identify key miRNAs that block ethanol effects. Aim 3 will identify pharmacological interventions that control miRNA-ndTF networks and prevent ethanol- mediated loss of NSCs. We will assess direct nAChR effects (i.e., varenicline exposure), as well as ndTF- and miRNA-mediated effects of nAChR activation, on NSC renewal and maturation. In these aims, we will manipulate ndTFs and miRNAs with innovative viral-mediated strategies, and a novel murine inducible reporter model to track affected NSCs and their daughter progeny. This proposal is significant in that it is expected to lay the theoretical and experimental framework for a new approach to address the un-met need for reparative fetal therapy to prevent FASD. It is innovative because it advances a novel conceptual model that links a cellular target (miRNA-ndTF networks) to a therapeutic approach (varenicline and nAChR pharmacology), to reprogram neurogenesis in the aftermath of alcohol exposure. As an outcome of these studies we expect to identify core molecular and pharmacological approaches to repair fetal damage following exposure to a potent and common teratogen, alcohol.

描述（由申请人提供）：由于美国普遍存在意外怀孕和酗酒模式，因此妊娠早期母亲饮酒是很难预防的，在妊娠第 1 个月，神经干细胞 (NSC) 暴露的情况很常见。开始产生神经元，增加神经发育障碍的风险，迫切需要生物医学干预措施来减轻酒精暴露的影响，这意味着我们无法帮助随后寻求酒精治疗的女性。我们的长期目标是找到减轻乙醇等致畸剂造成的脑损伤的方法。我们逆转乙醇影响的方法侧重于产前干预，以控制残留胎儿神经干细胞的生长潜力。我们的主要发现是，乙醇不会杀死 NSC，但会促进一类小调节 RNA（miRNA）介导许多乙醇效应。 (miR153、miR335) 控制 Nfia、Nfib 和 NeuroD1 等分化促进转录因子 (ndTF)，导致 NSC 中 ndTF 过早表达。此外，烟碱型乙酰胆碱受体 (nAChR) 激动剂可以防止甚至逆转乙醇对 miRNA 和 miRNA 的影响。总的来说，这些数据支持两个假设：（1）乙醇通过以下方式消耗 NSC。干扰 miRNA-ndTF 网络，防止 NSC 过早成熟；(2) miRNA 和 nAChR 激动剂都可以防止甚至逆转胎儿乙醇暴露的影响，目标 1 将确定促进乙醇对 NSC 自我更新和成熟的影响的关键 ndTF。目标 2 将确定阻断乙醇效应的关键 miRNA，目标 3 将确定控制 miRNA-ndTF 网络并防止乙醇介导的损失的药理学干预措施。我们将评估 nAChR 的直接影响（即伐尼克兰暴露）以及 nAChR 激活的 ndTF 和 miRNA 介导的影响，以实现这些目的，我们将通过创新的病毒介导的方法来操纵 ndTF 和 miRNA。策略，以及一种新颖的小鼠诱导报告模型来追踪受影响的 NSC 及其子代。该提案具有重要意义。预计将为一种新方法奠定理论和实验框架，以解决预防 FASD 的修复性胎儿治疗的未满足需求。它具有创新性，因为它提出了一种将细胞靶点（miRNA-ndTF 网络）与治疗方法（伐尼克兰和 nAChR 药理学），在酒精暴露后重新编程神经发生作为这些研究的结果，我们期望确定核心分子和药理学方法来修复暴露于强效且常见的致畸剂酒精后的胎儿损伤。