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（由适用提供）：母体乙醇的消费量已经并且仍然是对后代福祉的重要公共卫生关注。可以预防怀孕期间的禁欲，以及期望的公众外展和意识，在怀孕期间继续喝酒的女性中有很大一部分，有些甚至是贝吉饮料达到风险水平。怀孕期间乙醇的消费会导致胎儿酒精谱障碍（FASD），其标志是寿命长的神经行为和后代的认知异常。乙醇很容易穿过plapeta，并且在子宫内暴露于中等水平的乙醇的历史经常以不同程度的缺失神经行为和认知结果。然而，缺乏有效的FASD/FAS的有针对性治疗策略，或者充其量是不明显的。驱动该研究项目的总体内容是，需要更好地了解与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械假说，即乙醇破坏胚胎神经元中的氯化物稳态，并提出评估靶向氯化物共转运蛋白的治疗潜力，以制定和推进子宫内FASD药物干预的策略。我们提出了两个具体目的：特定目标1：检验假设的假设：NKCC1阻断剂Bumetanide可以防止或反应子宫乙醇对NKCC1介导的氯化物同种异体的影响，并减轻异常切向切向迁移。具体目的2：检验以下假设：在子宫内暴露于乙醇的年轻小鼠中，MPFC依赖性的逆转学习受损，而与乙酰乙醇相共处的小鼠则没有。 Bumetanide是一种经FDA批准的药物，已在人类中用作利尿剂治疗高血压的利尿剂。最近，由于发现GABA诱导的沉积可能在新生儿癫痫发作中发挥作用的原因，可甲烷酯治疗可降低低氧新生儿癫痫发作的大鼠模型中的癫痫发生，而Pilocarpine诱导的临时LOBE癫痫病则降低了癫痫发作，并且现在在1期临床试验中用于治疗过于氧化毒素的临床临床试验。在我们自己的初步支持数据的鼓励下，我们的目标是探索Bulkanide在防止或营救切向迁移缺陷以及结束神经行为和认知障碍的有效性，并在子宫暴露于乙醇中。一个基本目标是最大程度地降低胎儿的风险，但提供理想的利益。总体而言，NKCC1将首次成为药理目标，因为乙醇暴露对切向迁移，氯化物稳态以及长期神经行为和认知结果的潜在疗法。我们采用多级神经解剖学，电生理和行为方法来设定基础，并为未来的更全面的研究提供了希望，这将有望导致临床试验。提出的探索性研究是高度重要的，具有创新性的，高风险/高收益的，具有对FASD治疗管理的巨大影响。