Estradiol reduces mitochondrial oxidant stress in SNc DA neurons

雌二醇降低 SNc DA 神经元线粒体氧化应激

基本信息

批准号：
9591256
负责人：
Kristen Stout
金额：
$ 5.9万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2020-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9591256
关键词：
4-Hydroxy-Tamoxifen Achievement Acute Address Affect Animal Model Animals Automobile Driving Axon Basal Ganglia Behavior Bioenergetics Brain Calcium Cells Characteristics Communication Corpus striatum structure Coupled Data Dopamine Drug Design Electron Transport Electrons Electrophysiology (science)Ensure Enzymes Estradiol Estrogen Receptors Estrogen Therapy Estrogens Ethics Etiology Experimental Designs Female Genetic Genetic Techniques Goals Gonadal Steroid Hormones Incidence Laser Scanning Microscopy Levodopa Measures Mediating Mediator of activation protein Metabolism Methods Midbrain structure Mitochondria Mitochondrial Matrix Molecular Monitor Monoamine Oxidase Monoamine Oxidase A Monoamine Oxidase Inhibitors Movement Movement Disorders Mus Nerve Degeneration Neurotoxins Neurotransmitters Nitrogen Onset of illness Optics Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Oxygen Parkinson Disease Pathology Periodicity Pharmacology Postmenopause Premature Menopause Production Readiness Recycling Regulation Respiration Risk Role Scanning Science Signal Transduction Slice Stress Substantia nigra structure Technical Expertise Testing Time Training Woman Work career career development cost disorder risk dopaminergic neuron gain of function genetic approach human model improved inhibitor/antagonist insight male men mitochondrial dysfunction motor symptom neuroprotection oxidant stress oxidation pars compacta promoter response sensor sex tool two-photon young adult

项目摘要

Project Summary Selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) is a hallmark characteristic of Parkinson's disease (PD). PD is the most common neurodegenerative movement disorder and preferentially affects men, who have two-fold increased risk of PD incidence compared to women. Substantial evidence in humans and animal models of PD suggest estrogen is responsible for this decreased risk. How estrogen protects SNc DA neurons is not clear. Though the mechanisms underlying SNc DA neuron vulnerability are not fully understood, mitochondrial dysfunction is a clear contributor to PD pathology. SNc DA neurons are critical regulators of voluntary movement. Given the importance of voluntary movement to evolutionary survival, SNc DA neurons evolved redundant mechanisms to ensure ready calcium, neurotransmitter, and ATP sufficient to sustain prolonged release. Cav1 ca2+ channels help to establish SNc readiness by supporting pacemaking, stimulating DA synthesis, and triggering mitochondrial ATP production. Additionally, evidence suggests that dopamine metabolism via monoamine oxidase (MAO) stimulates mitochondrial ATP production. While these effects may provide short-term advantage, continual perpetual stimulation of mitochondrial respiration in SNc DA neurons generates reactive oxygen and nitrogen species, and increased mitochondrial damage and turnover. My preliminary data demonstrate that baseline mitochondrial oxidation in SNc DA axons of female mice is reduced compared to male mice. This effect was further increased by 17β-estradiol and eliminated by estrogen receptor inhibitor, 4-hydroxytamoxifen. There are two potential mediators of this effect. First, estrogen is an MAO inhibitor. Second, estrogen acutely and potently inhibits Cav1 ca2+ channels. Given this preliminary data, we hypothesize that estrogen protects SNc DA neurons by lowering axonal mitochondrial oxidant stress through two convergent mechanisms: 1) by diminishing MAO activity and 2) inhibiting Cav1 Ca2+ channels. We will test this hypothesis using two photon laser scanning microscopy in ex vivo brain slices of animals with targeted expression of fluorescent mitochondrial oxidation or calcium sensors coupled with rigorous pharmacology. Additionally, we will assess the contribution of 17β-estradiol to the bioenergetic demands of sustained dopamine release. In addition to addressing these timely and important questions, this project will provide advanced training in optical, electrophysiological, pharmacological, and genetic techniques, which, when coupled with training in scientific rigor from Drs. Surmeier and Woolley, will propel me to an independent and productive academic career.

项目摘要底虫nigra pars commacta（SNC）中多巴胺能（DA）神经元的选择性丧失是一个帕金森氏病（PD）的标志性特征。 PD是最常见的神经退行性运动障碍并优先影响男性，他们的PD发病率增加了两倍与女性相比。人类和PD动物模型的大量证据表明雌激素是负责这种降低的风险。雌激素如何保护SNC DA神经元尚不清楚。虽然 SNC DA神经元脆弱性的机制尚不完全了解，线粒体功能障碍是PD病理学的明显贡献者。 SNC DA神经元是关键的调节剂自愿运动。鉴于自愿运动对进化生存的重要性，SNC DA 神经元进化了冗余机制，以确保钙，神经递质和ATP 足以维持长时间的释放。 CAV1 CA2+频道有助于建立SNC准备就绪支持起搏，刺激DA合成并触发线粒体ATP的产生。此外，有证据表明多巴胺代谢通过氧化物（MAO）（MAO）刺激线粒体ATP产生。尽管这些影响可能会提供短期优势，但 SNC DA神经元中线粒体呼吸的连续永久刺激会产生反应性氧气和氮种，并增加了线粒体损伤和周转率。我的初步数据表明，雌性小鼠SNC DA轴突中的基线线粒体氧化减少与雄性小鼠相比。 17β-雌二醇进一步提高了这种作用，并通过雌激素受体抑制剂，4-羟基莫昔芬。这种效果有两个潜在的介体。首先，雌激素是MAO抑制剂。其次，雌激素急性，潜在地抑制Cav1 Ca2+ 频道。鉴于此初步数据，我们假设雌激素保护SNC DA神经元通过通过两种收敛机制降低轴突线粒体氧化应激：1）减少MAO活性和2）抑制CAV1 Ca2+通道。我们将检验这个假设在具有目标的动物的离体脑切片中使用两个光子激光扫描显微镜荧光线粒体氧化或钙传感器的表达与严格药理。此外，我们将评估17β-雌二醇对生物能的贡献持续多巴胺释放的需求。除了解决这些及时和重要的问题问题，该项目将提供光学，电生理学的高级培训，药理学和遗传技术，当与科学严谨的培训相结合时博士。 Surmeier和Woolley将使我进入独立和产品学术生涯。