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: 10322760
• 负责人: Brendan J Dougherty
• 金额: $ 44.97万
• 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/10322760
• 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; Work; base; flexibility; genetic manipulation; hormonal signals; inhibitor; innovation; knock-down; male; neurophysiology; neuroregulation; novel; 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.

项目摘要/摘要 呼吸控制系统显示出显着的神经塑性能力，赋予了呼吸的灵活性 响应整个生命周期的身体或环境状况的变化。性腺恐怖 （雌激素，孕激素，雄激素）发挥强大的调节作用，直接影响 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。指导这一提议的总体假设是 脊髓内的性腺荷鸟信号传导是必要的，以表达呼吸 神经可塑性通过调节脊柱小胶质细胞。五个重要的初步发现支持这一点 假设。首先，虽然雌激素和孕激素通常是作为主要性腺恐怖症 雌性，而雄激素被认为是雄性的主要性腺恐怖剂，实际上是雌二醇 允许呼吸神经可塑性所需的性别。其次，将睾丸激素芳香化至雌二醇 直接在脊髓内，以引起男性的可塑性。第三，雌激素受体同工型（ERα，ERβ和 GPER）对于使呼吸可塑性至关重要，在女性和男性中是独一无二的。第四，雌二醇 补充或脊柱雌激素受体的药物激活足以挽救可塑性 在两性中的性腺去除后。第五，用局部抗炎药治疗脊髓 或减少CNS小胶质细胞的种群（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，表明脊柱小胶质细胞在 雌激素诱导的可塑性恢复。使用严格的呼吸神经塑性的神经生理学测量 结合雌激素受体药理学，siRNA敲低的靶向基因操纵，流量 细胞仪，质谱和蛋白质生物化学，我们将剖析脊柱雌激素受体的作用 表达呼吸神经可塑性的信号。将测试三个特定的假设：1）脊柱ER 信号对于诱导女性和雌性大鼠的呼吸神经塑性是必需的。 2）脊柱雌激素 当性别立体声水平全身降低时，信号足以恢复呼吸可塑性； 3） 雌激素通过调节脊髓小胶质细胞允许呼吸可塑性。这些研究解决了 在我们对呼吸神经功能的基本生物学理解中的关键差距；性爱的信号如何 能够发展呼吸神经可塑性。此外，我们的结果将直接告知正在进行的 转化研究针对呼吸神经可塑性的机制，以进行治疗益处。