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（由适用提供）：由于计划外怀孕和美国饮酒的暴饮暴食模式，因此难以预防怀孕初期的产妇饮酒。当神经固醇细胞（NSC）开始产生神经元时，暴露是常见的，从而增加了神经发育障碍的风险。生物医学干预措施减轻酒精暴露的影响至关重要，无限制。缺乏这样的干预措施意味着我们几乎无能为力帮助那些随后寻求产前护理胎儿酒精的妇女。我们的长期目标是找到通过像乙醇这样的破坏者引起的减轻脑损伤的方法。我们逆转乙醇作用的方法着重于在产前介入以操纵残留胎儿NSC的生长潜力。这种方法是基于我们的关键发现，即乙醇不会杀死NSC，而是促进过早成熟。一类小的监管RNA，miRNA介导了许多乙醇作用。乙醇取消了miRNA（miR153，miR335）控制分化促进转录因子（NDTFS），例如NFIA和NFIB和NFIB和NEUROD1，从而导致NSC中的NDTF表达过早。此外，烟碱乙酰胆碱受体（NACHR）激动剂可以预防乙醇对miRNA及其靶NDTF的影响。总的来说，这些数据支持两个假设：（1）乙醇通过干扰防止过早NSC成熟的miRNA-NDTF网络来耗尽NSC，（2）miRNA和NACHR激动剂都可以预防胎儿乙醇暴露，甚至可以逆转。 AIM 1将确定促进乙醇对NSC自我更新和成熟的影响的关键NDTF，而AIM 2将识别阻断乙醇影响的关键miRNA。 AIM 3将确定控制miRNA-NDTF网络并防止乙醇介导的NSC损失的药理干预措施。我们将评估直接的NACHR效应（即Varenicline暴露），以及NSC恢复和成熟的NDTF和miRNA介导的效果。在这些目标中，我们将使用创新的病毒介导的策略来操纵NDTF和miRNA，以及一种新颖的鼠诱导记者模型来跟踪受影响的NSC及其女儿后代。该提议很重要，因为它是预计将建立一种理论和实验框架，用于一种新的方法，以满足未MET对预防FASD的修复胎儿疗法的需求。之所以具有创新性，是因为它推进了一种新型的概念模型，该模型将细胞靶（miRNA-NDTF网络）与治疗方法（VARENICLINE和NACHR药理学）联系起来，以在酒精暴露后重编程神经发生。作为这些研究的结果，我们期望鉴定出暴露于潜在的和普通的伤明，酒精后修复胎儿损害的核心分子和药理方法。