Estrogen Receptor Signaling in the Expression of Respiratory Motor Plasticity

呼吸运动可塑性表达中的雌激素受体信号传导

• 批准号: 10545064
• 负责人: Brendan J Dougherty
• 金额: $ 44.66万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10545064
• 关键词: Address; Androgens; Anti-Inflammatory Agents; Area; Biological; Biological Availability; Breathing; CSF1R gene; Cervical spinal cord structure; Characteristics; Data; Development; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Excision; Female; Flow Cytometry; GPER gene; Gonadal Hormones; Gonadal Steroid Hormones; Gonadal structure; Knowledge; Longevity; Mass Spectrum Analysis; Measures; Microglia; Molecular; Motor; Motor Neurons; Neurobiology; Neuronal Plasticity; Neurophysiology - biologic function; Pharmacology; Physiological; Population; Progestins; Protein Biochemistry; Protein Isoforms; Rattus; Receptor Signaling; Recovery; Regulation; Reporting; Research; Research Infrastructure; Research Personnel; Respiration; Role; Sex Differences; Signal Transduction; Small Interfering RNA; Spinal; Spinal Cord; Supplementation; System; Testing; Testosterone; Therapeutic; Vertebral column; Work; flexibility; genetic manipulation; hormonal signals; inhibitor; innovation; knock-down; male; neurophysiology; neuroregulation; novel; pharmacologic; respiratory; response; sex; sexual dimorphism; siRNA delivery; targeted delivery; translational study; virtual

PROJECT SUMMARY/ABSTRACT The respiratory control system displays a remarkable capacity for neuroplasticity, imparting flexibility of breathing in response to changing physiological or environmental conditions across the lifespan. Gonadal hormones (estrogens, progestins, androgens) exert powerful modulatory effects and directly influence the development of neuroplasticity in other neural control areas. Yet, the role of gonadal hormone signaling in the development respiratory neuroplasticity has not been clearly defined. The overarching hypothesis guiding this proposal is that gonadal hormone signaling within the spinal cord is necessary to enable expression of respiratory neuroplasticity through regulation of spinal microglia. Five important preliminary findings support this hypothesis. First, while estrogens and progestins are typically associated as the principal gonadal hormones in females, whereas androgens are considered the primary gonadal hormone in males, it is in fact estradiol in both sexes that is required to permit respiratory neuroplasticity. Second, testosterone is aromatized to estradiol directly within the spinal cord to elicit plasticity in males. Third, the estrogen receptor isoforms (ERα, ERβ and GPER) essential for enabling respiratory plasticity are unique in females and males. Fourth, estradiol supplementation or the pharmacological activation of spinal estrogen receptors is sufficient to rescue plasticity following removal of the gonads in both sexes. Fifth, treating the spinal cord with a localized anti-inflammatory, or reducing the population of CNS microglia (using a CSF1R inhibitor), is sufficient to restore respiratory neuroplasticity in rats of both sexes following removal of the gonads, indicating a role for spinal microglia in the estrogen-induced recovery of plasticity. Using rigorous neurophysiologic measures of respiratory neuroplasticity in combination with estrogen receptor pharmacology, targeted gene manipulation by siRNA knockdown, flow cytometry, mass spectroscopy, and protein biochemistry, we will dissect the role of spinal estrogen receptor signaling for expression of respiratory neuroplasticity. Three specific hypotheses will be tested: 1) Spinal ER signaling is necessary for induction of respiratory neuroplasticity in female and male rats; 2) Spinal estrogen signaling is sufficient to restore respiratory plasticity when sex steroid levels are systemically reduced; and 3) Estrogen permits respiratory plasticity through modulation of spinal cord microglia. These studies address a critical gap in our basic biological understanding of respiratory neural function; how sex hormone signaling enables development of respiratory neuroplasticity. In addition, our results will directly inform ongoing translational studies targeting mechanisms of respiratory neuroplasticity for therapeutic benefit.

项目概要/摘要 呼吸控制系统表现出卓越的神经可塑性，赋予呼吸灵活性 响应生命周期中不断变化的生理或环境条件。性腺激素 （雌激素、孕激素、雄激素）发挥强大的调节作用，直接影响发育 其他神经控制区域的神经可塑性。然而，性腺激素信号在发育中的作用 呼吸神经可塑性尚未明确定义。指导该提案的总体假设是 脊髓内的性腺激素信号传导对于呼吸系统表达是必要的 通过调节脊髓小胶质细胞实现神经可塑性。五项重要的初步发现支持了这一点 假设。首先，虽然雌激素和孕激素通常被认为是主要的性腺激素， 女性中，雄激素被认为是男性的主要性腺激素，但实际上，男性和女性中的雄激素都是雌二醇 允许呼吸神经可塑性所需的性别。其次，睾酮芳香化为雌二醇 直接在脊髓内激发男性的可塑性。第三，雌激素受体亚型（ERα、ERβ和 GPER）对于实现呼吸可塑性至关重要，在女性和男性中是独一无二的。四、雌二醇 补充或药物激活脊髓雌激素受体足以挽救可塑性 去除两性的性腺后。第五，用局部抗炎药治疗脊髓， 或减少中枢神经系统小胶质细胞的数量（使用 CSF1R 抑制剂），足以恢复呼吸系统 去除性腺后两性大鼠的神经可塑性，表明脊髓小胶质细胞在 雌激素诱导的可塑性恢复。使用严格的神经生理学措施测量呼吸神经可塑性 结合雌激素受体药理学，通过 siRNA 敲低进行靶向基因操作，流程 细胞计数、质谱和蛋白质生物化学，我们将剖析脊髓雌激素受体的作用 呼吸神经可塑性表达的信号传导。将测试三个具体假设：1) 脊髓 ER 信号传导对于诱导雌性和雄性大鼠的呼吸神经可塑性是必要的； 2) 脊髓雌激素 当性类固醇水平全身降低时，信号传导足以恢复呼吸可塑性；和 3) 雌激素通过调节脊髓小胶质细胞实现呼吸可塑性。这些研究解决了 我们对呼吸神经功能的基本生物学理解存在重大差距；性激素如何传递信号 促进呼吸神经可塑性的发展。此外，我们的结果将直接告知正在进行的 针对呼吸神经可塑性机制以获得治疗益处的转化研究。