Pharmacologically targeting the NKCC1 chloride cotransporter in utero for FASD

子宫内 NKCC1 氯化物协同转运蛋白的药理学靶向治疗 FASD

• 批准号: 9132153
• 负责人: Hermes H Yeh
• 金额: $ 19.24万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132153
• 关键词: Abstinence; Acute; Alcohol consumption; Alcohols; Automobile Driving; Awareness; Behavioral; Brain; Bumetanide; Cells; Centers for Disease Control and Prevention (U.S.); Child; Chloride Ion; Chlorides; Clinical Trials; Cognitive; Counseling; Data; Defect; Development; Diuretics; Drug effect disorder; Effectiveness; Electrophysiology (science); Embryo; Embryonic Development; Environment; Epilepsy; Ethanol; Event; Exploratory/Developmental Grant; FDA approved; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetus; Future; Goals; Homeostasis; Human; Hyperactive behavior; Hypoxia; Immigration; Impaired cognition; Impairment; Individual; Infant; Interneurons; Intervention; Investigation; Label; Lead; Life; Longevity; Medial; Mediating; Membrane; Modeling; Molecular; Mothers; Movement; Mus; National Institute on Alcohol Abuse and Alcoholism; Nature; Neonatal; Neurons; Outcome; Patient Self-Report; Perinatal Exposure; Pharmaceutical Preparations; Phase I Clinical Trials; Pilocarpine; Placenta; Play; Prefrontal Cortex; Pregnancy; Preventive; Process; Protein Isoforms; Public Health; Rattus; Recording of previous events; Regimen; Research; Research Project Grants; Reversal Learning; Risk; Role; Seizures; Slice; Staging; Strategic Planning; Temporal Lobe Epilepsy; Testing; Therapeutic; Time; Transgenic Organisms; Video Microscopy; Vision; Woman; Work; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; alcohol measurement; binge drinking; drinking; gamma-Aminobutyric Acid; high risk; hypertension treatment; in utero; innovation; migration; neurobehavior; neurobehavioral; neurobehavioral test; novel; offspring; outreach; preclinical study; prevent; public health relevance; receptor; receptor function; socioeconomics; symporter; targeted treatment; young adult

 DESCRIPTION (provided by applicant): Maternal ethanol consumption has been and remains a significant public health concern for the wellbeing of the progeny. Preventable as it is by abstinence during pregnancy, and despite public outreach and awareness, a significant percentage of women continue to drink during pregnancy, some even binge drink to risky levels. Consumption of ethanol during pregnancy can lead to fetal alcohol spectrum disorders (FASD), hallmarked by life- long neurobehavioral and cognitive abnormalities in the offspring. Ethanol readily crosses the placenta, and children with history of having been exposed in utero to even moderate levels of ethanol frequently present with varying degrees of deleterious neurobehavioral and cognitive outcomes. Yet, effective targeted treatment strategies for FASD/FAS are lacking or at best ill defined. The overarching contention driving this research project is that a better understanding of the cellular and molecular underpinnings of FASD-associated abnormalities is needed. To this end, we will test a novel mechanistic hypothesis that ethanol disrupts chloride homeostasis in embryonic neurons, and propose to assess the therapeutic potential of targeting chloride co-transporters in order to develop and advance strategies for the pharmacological intervention of FASD in utero. We propose two specific aims: Specific Aim 1: Test the hypothesis that bumetanide, an NKCC1 blocker, prevents or rescues in utero ethanol's effect on NKCC1-mediated chloride homoeostasis and mitigates the abnormal tangential migration. Specific Aim 2: Test the hypothesis that mPFC-dependent reversal learning is impaired in young adult mice exposed in utero to ethanol but not in those co-treated with bumetanide. Bumetanide is an FDA-approved drug that has been used therapeutically in humans as a diuretic agent in treatment of hypertension. More recently, prompted by the finding that GABA-induced depolarization may play a role in neonatal seizures, bumetanide treatment was shown to decrease epileptic events in rat models of hypoxic neonatal seizures and pilocarpine-induced temporal lobe epilepsy and is now in Phase 1 clinical trials for treating infants with hypoxic neonatal seizures. Encouraged by our own preliminary supporting data, our goal is to explore the effectiveness of bumetanide in preventing or rescuing the tangential migration defect and enduring neurobehavioral and cognitive impairment seen with in utero exposure to ethanol. An underlying goal is to minimize the risk to the fetus yet provide the desired benefit. Overall, NKCC1 will be pharmacologically targeted for the first time as potential therapy for the untoward effects of ethanol exposure on tangential migration, chloride homeostasis and long-term neurobehavioral and cognitive outcomes. We take a multi-level neuroanatomical, electrophysiological and behavioral approach to set the groundwork and inform future more comprehensive studies that will hopefully lead to clinical trials. The exploratory studies proposed are highly significant and innovative, high risk/high yield, with great potential for translational impact on the therapeutic management of FASD.

 描述(由申请人提供)：母亲的酒精消费一直是并仍然是一个严重的公共卫生问题，关系到后代的福祉。尽管在怀孕期间禁酒是可以预防的，尽管公众宣传和认识到了这一点，但仍有相当一部分妇女在怀孕期间继续饮酒，有些人甚至狂饮到危险的程度。怀孕期间摄入酒精可导致胎儿酒精谱系障碍(FASD)，其特征是后代出现终生神经行为和认知异常。乙醇很容易通过胎盘，有宫内接触过中等水平乙醇的儿童经常会出现不同程度的有害神经行为和认知结果。然而，对于FASD/Fas缺乏有效的靶向治疗策略，或者充其量是定义不清的。推动这项研究项目的主要论点是，需要更好地了解FASD相关异常的细胞和分子基础。为此，我们将检验一个新的机制假说，即乙醇破坏胚胎神经元的氯离子稳态，并建议评估靶向氯离子共转运体的治疗潜力，以开发和推进FASD在宫内的药物干预策略。我们提出了两个特定的目标：特定的目标1：验证NKCC1阻断剂布美他尼在子宫内阻止或挽救乙醇对NKCC1介导的氯离子稳态的影响并减轻异常的切向迁移的假设。具体目标2：验证这样的假设，即子宫内暴露于乙醇的年轻成年小鼠依赖mPFC的逆转学习受到损害，但在布美他尼联合治疗的小鼠中不受影响。布美他尼是FDA批准的一种药物，已在人类治疗中用作利尿剂治疗高血压。最近，在GABA诱导的去极化可能在新生儿癫痫发作中发挥作用的发现的推动下，布美他尼治疗被证明可以减少缺氧性新生儿癫痫和匹罗卡品诱导的颞叶癫痫大鼠模型的癫痫事件，目前正处于治疗婴儿缺氧性新生儿癫痫的第一阶段临床试验。在我们自己的初步支持数据的鼓舞下，我们的目标是探索布美他尼在预防或挽救子宫内乙醇暴露所见的切向迁移缺陷和持久的神经行为和认知障碍方面的有效性。一个潜在的目标是将对胎儿的风险降至最低，同时提供预期的好处。总体而言，NKCC1将首次作为潜在的治疗药物，用于治疗乙醇暴露对切向迁移、氯离子稳态以及长期神经行为和认知结果的不良影响。我们采取多层次的神经解剖学、电生理学和行为学方法来奠定基础，并为未来更全面的研究提供信息，这些研究有望导致临床试验。提出的探索性研究具有重要意义和创新性，高风险/高收益，对FASD的治疗管理具有巨大的转化性影响。