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）：母亲的乙醇消耗一直是并且仍然是影响后代福祉的重要公共卫生问题。尽管可以通过怀孕期间禁酒来预防，但尽管公众进行了宣传和提高了认识，但仍有相当大比例的女性在怀孕期间继续饮酒，有些甚至酗酒到危险水平。怀孕期间摄入乙醇可导致胎儿酒精谱系障碍 (FASD)，其特点是后代终生神经行为和认知异常。乙醇很容易穿过胎盘，有在子宫内接触过中等水平乙醇史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，针对 FASD/FAS 的有效靶向治疗策略尚缺乏，或者充其量是不明确的。推动该研究项目的首要论点是，需要更好地了解 FASD 相关异常的细胞和分子基础。为此，我们将测试一种新的机制假设，即乙醇会破坏胚胎神经元中的氯稳态，并建议评估靶向氯协同转运蛋白的治疗潜力，以便制定和推进子宫内 FASD 的药物干预策略。我们提出了两个具体目标： 具体目标 1：测试以下假设：布美他尼（一种 NKCC1 阻断剂）可预防或挽救子宫内乙醇对 NKCC1 介导的氯离子稳态的影响，并减轻异常切向迁移。具体目标 2：检验以下假设：在子宫内暴露于乙醇的年轻成年小鼠中，mPFC 依赖性逆转学习受到损害，但与布美他尼联合治疗的小鼠则没有。 布美他尼是 FDA 批准的药物，已在人类中作为治疗高血压的利尿剂。最近，由于发现 GABA 诱导的去极化可能在新生儿癫痫发作中发挥作用，布美他尼治疗在缺氧新生儿癫痫发作和毛果芸香碱诱导的颞叶癫痫大鼠模型中被证明可以减少癫痫事件，目前正处于治疗婴儿缺氧新生儿癫痫发作的 1 期临床试验中。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因子宫内接触乙醇而出现的切向迁移缺陷以及持久性神经行为和认知障碍方面的有效性。根本目标是最大限度地降低胎儿的风险，同时提供所需的益处。总体而言，NKCC1 将首次成为药理学目标，作为潜在疗法，治疗乙醇暴露对切向迁移、氯稳态以及长期神经行为和认知结果的不良影响。我们采用多层次的神经解剖学、电生理学和行为方法来奠定基础，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。所提出的探索性研究具有高度意义和创新性、高风险/高收益，对 FASD 的治疗管理具有巨大的转化影响潜力。