Prenatal microRNA neuro-therapeutics for fetal alcohol exposure

针对胎儿酒精暴露的产前 microRNA 神经疗法

• 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
• 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' 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

 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）：由于美国计划外怀孕和酗酒模式的普遍存在，孕妇在怀孕早期饮酒很难预防。暴露在妊娠早期是常见的，此时神经干细胞（NSC）开始产生神经元，增加了神经发育障碍的风险。有一个关键的，未满足的需要，生物医学干预措施，以减轻酒精暴露的影响。缺乏这样的干预措施意味着我们对那些随后因胎儿酒精暴露而寻求产前护理的妇女几乎无能为力。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集中在产前干预，以操纵残留胎儿神经干细胞的生长潜力。这种方法基于我们的关键发现，即乙醇不会杀死神经干细胞，但会促进过早成熟。一类小的调节RNA，miRNA，介导了许多这些乙醇效应。乙醇使miRNA（miR 153、miR 335）对Nfia、Nfib和NeuroD 1等分化促进转录因子（ndTF）的控制失调，导致NSC中的ndTF过早表达。此外，烟碱乙酰胆碱受体（nAChR）激动剂可以防止甚至逆转乙醇对miRNA及其靶向ndTF的作用。总的来说，这些数据支持两个假设：（1）乙醇通过干扰miRNA-ndTF网络来减少NSC，从而防止NSC过早成熟，以及（2）miRNA和nAChR激动剂都可以预防甚至逆转胎儿乙醇暴露的影响。目标1将鉴定促进乙醇对NSC自我更新和成熟的作用的关键ndTF，而目标2将鉴定阻断乙醇作用的关键miRNAs。目的3将鉴定控制miRNA-ndTF网络并防止乙醇介导的NSC损失的药理学干预。我们将评估nAChR的直接影响（即，伐尼克兰暴露），以及ndTF和miRNA介导的nAChR活化对NSC更新和成熟的影响。在这些目标中，我们将利用创新的病毒介导的策略操纵ndTF和miRNA，以及一种新的小鼠诱导型报告模型来跟踪受影响的NSC及其子代。这一建议的重要性在于， 预期为新方法奠定理论和实验框架，以解决未满足的胎儿修复治疗预防FASD的需求。它是创新的，因为它提出了一种新的概念模型，将细胞靶点（miRNA-ndTF网络）与治疗方法（伐尼克兰和nAChR药理学）联系起来，在酒精暴露后重新编程神经发生。作为这些研究的结果，我们希望确定核心的分子和药理学方法，以修复胎儿损伤后，暴露于一个强大的和常见的致畸剂，酒精。