The chloride cotransporter NKCC1 in the embryonic etiology and treatment of FASD

氯协同转运蛋白 NKCC1 在 FASD 胚胎病因学和治疗中的作用

• 批准号: 10675600
• 负责人: Hermes H Yeh
• 金额: $ 50.31万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10675600
• 关键词: Abstinence; Acceleration; Acute; Address; Affect; Alcohol consumption; Alcohols; Attention; Automobile Driving; Behavioral; Bumetanide; Child; Chlorides; Cognitive; Companions; Consumption; Control Groups; Counseling; Defect; Electrophysiology (science); Embryo; Embryonic Development; Environment; Equilibrium; Ethanol; Etiology; FDA approved; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Future; Glutamates; Height; Homeostasis; Hyperactivity; Impairment; Individual; Interneurons; Intervention; Investigation; Knowledge; Label; Life; Light; Longevity; Medial; Mediating; Membrane Potentials; Molecular; Mothers; Mus; National Institute on Alcohol Abuse and Alcoholism; Neuroanatomy; Neurons; Neurotransmitter Receptor; Outcome; Perforation; Personal Satisfaction; Pharmaceutical Preparations; Play; Prefrontal Cortex; Pregnancy; Pregnant Women; Prevention; Process; Protein Isoforms; Public Health; Recording of previous events; Regimen; Research; Research Project Grants; Rest; Reversal Learning; Slice; Strategic Planning; Strategic vision; Synapses; Synaptic Transmission; Testing; Therapeutic; Time; Woman; Work; adverse outcome; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; alcohol measurement; antagonist; behavior test; cell motility; experience; experimental study; flexibility; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in utero; innovation; male; migration; neurobehavior; neurobehavioral; neurobehavioral test; neurotransmission; novel; offspring; outreach; pharmacologic; postnatal; prenatal exposure; prenatal therapy; prevent; rational design; receptor; receptor function; symporter; synaptic function; targeted treatment; translational potential; treatment strategy; young adult

ABSTRACT Preventable as it is by abstinence during pregnancy, maternal ethanol consumption is a significant public health concern because a significant percentage of pregnant women drink; 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. Indeed, 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 ill defined. The overarching impetus 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. Specific Aim 1: Test the hypothesis that blocking the function of NKCC1 with its antagonist bumetanide prevents and/or rescues ethanol’s effect on chloride homoeostasis in migrating embryonic GABAergic cortical interneurons and mitigates their abnormal tangential migration due to ethanol exposure in utero. Specific Aim 2: Test the hypothesis that bumetanide treatment prevents and/or rescues the impaired mPFC- dependent behavioral flexibility and attentional capacity in young adult mice exposed in utero to ethanol. Specific Aim 3: Test the hypothesis that bumetanide treatment prevents and/or rescues the (1) altered number and/or distribution of GABAergic cortical interneurons and/or (2) abnormal GABAergic and glutamatergic neurotransmission in the mPFC of young adult mice exposed in utero to ethanol. Our previous work established that GABA promotes the tangential migration of GABAergic cortical interneurons, and that ethanol affects this process to result in an “interneuronopathy” with enduring adverse consequences on cortical form, synaptic function and neurobehavior. However, the mechanism underlying this interneuronopathy is not known. The three specific aims will fill this knowledge gap and, in so doing, advance our understanding of the etiology underlying FASD. Overall, for the first time, NKCC1 will be investigated as a key unifying mechanism underlying the untoward effects of ethanol exposure in utero on tangential migration, chloride homeostasis and long- term neurobehavioral and cognitive outcomes, and pharmacologically targeted as potential therapy for FASD. In this light, this proposal addresses pressing questions in FASD that are highly significant, taking a multi-level neuroanatomical, electrophysiological and behavioral approach that is innovative, impactful, with great potential for shedding light on the therapeutic management of FASD.

抽象的 可以预防怀孕期间的禁欲，孕产妇消费是重要的公共卫生 关心，因为很大一部分孕妇饮酒；有些甚至Benge饮酒达到风险水平。 怀孕期间乙醇的消费会导致胎儿酒精谱系（FASD），其标志是生命的标志 后代长长的神经行为和认知异常。确实，有历史的孩子 在子宫内暴露于中等水平的乙醇，经常出现不同程度的有害 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 定义。推动该研究项目的总体动力是对细胞和细胞的更好理解 需要与FASD相关异常的分子基础。为此，我们将测试一种新颖的机械 假设乙醇会破坏胚胎神经元中的氯化物稳态，并提出评估疗法的提议 靶向氯化物共转运蛋白的潜力，以制定和推进药物的策略 FASD在子宫内的干预。 特定目的1：测试以下假设：阻止NKCC1的拮抗剂busetanide阻止 和/或反应乙醇对氯化物同种异体的影响 并减轻由于子宫内乙醇暴露而导致的绝对切向迁移。 特定目标2：检验bumetanide治疗可防止和/或反应受损的MPFC-的假设。 子宫内暴露于乙醇的年轻小鼠的依赖行为灵活性和注意力能力。 特定目的3：测试bumetanide治疗可防止和/或响应（1）变化数的假设 和/或或分布GABA能皮质中间神经元和/或（2）异常的GABA能和谷氨酸能 在子宫内暴露于乙醇的年轻小鼠MPFC中的神经传递。 我们以前的工作确定GABA促进了GABA能皮质中间神经元的切向迁移， 乙醇会影响这一过程，导致“神经间疾病”，并对 皮质形式，突触功能和神经行为。但是，这种神经间病间病的机制是 不知道。这三个具体目标将填补这一知识差距，并在此过程中提高我们对 基础FASD的病因。总体而言，NKCC1将首次作为关键统一机制进行研究 乙醇暴露在子宫内对切向迁移，氯化物稳态和长期的不良影响的基础 术语神经行为和认知结果，并以药物为目标是对FASD的潜在治疗。在这个 该提案在FASD中提出了非常重要的问题，该提案涉及多层次的迫切问题 具有创新性，有影响力的神经解剖学，电生理和行为方法，具有巨大潜力 阐明FASD的治疗管理。