Female Sex Hormones and Spinal Injury

描述（由申请人提供）：我们建议确定内源性和外源性女性性激素对颈脊髓损伤（SCI）损伤的最关键运动功能（呼吸）恢复的影响。虽然内源性雌激素和孕激素促进创伤性脑损伤后的恢复，但它们对SCI后运动恢复的影响尚不清楚。雌性啮齿动物发情周期中这些激素的波动表明，潜在的“神经保护”作用可能取决于损伤的时间。指导该建议的第一个假设是，SCI时的动情周期阶段和相应的孕酮（一种雌激素）和17 β-雌二醇（一种雌激素）水平与运动恢复相关（目标1）。外源性孕酮和17 β-雌二醇的给药已被证明可以改善SCI后的运动恢复。然而，这些激素也是强大的呼吸兴奋剂。PI收集的数据和其他研究表明，脊髓损伤后的呼吸刺激加强了对膈运动神经元的现有脊髓突触输入。因此，针对呼吸功能不全的性激素治疗可以将联合收割机的普遍神经保护作用与膈运动系统的特异性作用结合起来。因此，我们的第二个假设是，外源性孕酮和17 β-雌二醇的管理后，颈椎脊髓损伤将改善呼吸运动恢复（目的2）。将使用大鼠的行为、神经生理学和免疫测定技术对这些假设进行检验。将通过气压体积描记法在未麻醉大鼠中评估通气。将在麻醉下量化膈输出，并将用ELISA测量血浆激素水平。这些数据将有助于确定1）内源性性别激素是否可以影响临床前SCI研究，以及2）孕酮和17 β-雌二醇激素治疗是否是促进颈椎SCI后持续呼吸恢复的有效手段。

DESCRIPTION (provided by applicant): We propose to determine the effects of endogenous and exogenous female sex hormones on recovery of perhaps the most critical motor function impaired by cervical spinal cord injury (SCI): breathing. Although endogenous estrogens and progestins promote recovery following traumatic brain injury, their impact on motor recovery after SCI is unknown. Fluctuations in these hormones during the estrous cycle in female rodents suggest that potential "neuroprotective" effects may depend on the time of the injury. The first hypothesis guiding this proposal is that the estrous cycle stage and corresponding levels of progesterone (a progestin) and 17beta-estradiol (an estrogen) at the time of SCI will correlate with motor recovery (Aim 1). Administration of exogenous progesterone and 17beta-estradiol has been shown to improve locomotor recovery after SCI. However, these hormones are also powerful respiratory stimulants. Data collected by the P.I. and others indicates that respiratory stimulation after SCI strengthens existing spinal synaptic inputs to phrenic motoneurons. Thus, sex hormone therapy targeting respiratory insufficiency may combine generalized neuroprotective effects with effects specific to the phrenic motor system. Accordingly, our second hypothesis is that administration of exogenous progesterone and 17beta-estradiol after cervical SCI will improve respiratory motor recovery (Aim 2). These hypotheses will be tested using behavioral, neurophysiological, and immunoassay techniques in rats. Ventilation will be assessed in unanesthetized rats via barometric plethysmography. Phrenic output will be quantified under anesthesia, and plasma hormone levels will be measured with ELISA. These data will help establish 1) if endogenous gender hormones can influence preclinical SCI research, and 2) if progesterone and 17p-estradiol hormone therapy is an effective means of promoting persistent respiratory recovery following cervical SCI.