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.

项目概要黑质致密部 (SNc) 中多巴胺能 (DA) 神经元的选择性丧失是一种帕金森病 (PD) 的标志性特征是最常见的神经退行性疾病。运动障碍，尤其影响男性，他们患 PD 的风险增加两倍与女性相比，人类和动物帕金森病模型中的大量证据表明雌激素是尽管雌激素如何保护 SNc DA 神经元，但其机制尚不清楚。 SNc DA 神经元脆弱性的机制尚不完全清楚，线粒体功能障碍是 PD 病理学的一个明显因素。 SNc DA 神经元是 PD 病理学的关键调节因子。鉴于自愿运动对进化生存的重要性，SNc DA 神经元进化出冗余机制来确保钙、神经递质和 ATP 准备就绪足以维持长时间释放 Cav1 ca2+ 通道有助于建立 SNc 准备状态。支持起搏、刺激 DA 合成并触发线粒体 ATP 产生。此外，有证据表明多巴胺通过单胺氧化酶（MAO）代谢虽然这些效应可能会提供短期优势， SNc DA 神经元线粒体呼吸的持续永久刺激会产生反应性氧和氮的种类，以及线粒体损伤和周转的增加。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-雌二醇进一步增强了这种效应，而 17β-雌二醇则消除了这种效应。雌激素受体抑制剂，4-羟基他莫昔芬有两种潜在的调节剂。首先，雌激素是一种 MAO 抑制剂，其次，雌激素可强烈且有效地抑制 Cav1 ca2+。根据这些初步数据，我们认为雌激素可以保护 SNc DA 神经元。通过两种趋同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+ 通道我们将检验这一假设。使用两个光子激光扫描显微镜对动物的离体脑切片进行靶向荧光线粒体氧化或钙传感器的表达加上严格的此外，我们将评估 17β-雌二醇对生物能的贡献。除了及时且重要地解决这些问题之外，还需要持续释放多巴胺。问题，该项目将提供光学、电生理学、药理学和遗传技术，与科学严谨的培训相结合 Surmeier 博士和 Woolley 博士将推动我走向独立且富有成效的学术生涯。