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

基本信息

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
项目类别：
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

项目摘要

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）：母亲的乙醇消费一直是并且仍然是影响后代福祉的一个重大公共卫生问题，可以通过怀孕期间的禁酒来预防，尽管公众宣传和提高了认识，但仍有相当大比例的妇女继续饮酒。在怀孕期间，有些人甚至在怀孕期间酗酒到危险水平会导致胎儿酒精谱系障碍（FASD），其特点是后代的终生神经行为和认知异常。乙醇很容易穿过胎盘，即使是在子宫内接触过中等水平乙醇的儿童也经常出现不同程度的有害神经行为和认知结果，然而，针对 FASD/FAS 的有效针对性治疗策略仍然缺乏或最多是患病。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。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：检验以下假设：布美他尼是一种 NKCC1 阻滞剂，可预防或挽救子宫内乙醇对 NKCC1 介导的氯稳态的影响，并减轻异常切向具体目标 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（布美他尼）联合治疗的小鼠却没有受到损害。布美他尼是 FDA 批准的一种药物，已用于人类治疗。作为治疗高血压的利尿剂，最近发现 GABA 诱导的去极化可能在新生儿癫痫发作中发挥作用，布美他尼治疗被证明可以减少大鼠的癫痫事件。我们建立了新生儿缺氧性癫痫发作和毛果芸香碱诱发的颞叶癫痫模型，目前正处于治疗新生儿缺氧性癫痫发作的一期临床试验中，受我们自己的初步支持数据的鼓舞，我们的目标是探索布美他尼在预防或挽救新生儿缺氧性癫痫方面的有效性。子宫内接触乙醇会导致切向迁移缺陷和持久的神经行为和认知障碍。一个根本目标是最大限度地降低胎儿的风险，同时提供保护。总体而言，NKCC1 将首次在药理学上作为潜在疗法来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。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，这些探索性研究具有高度意义和创新性，高风险/高收益，具有巨大的潜力。对 FASD 治疗管理的转化影响。