The role of gender on post-traumatic inflammation

性别对创伤后炎症的作用

• 批准号: 6580120
• 负责人: Helen M Bramlett
• 金额: $ 20.35万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6580120
• 关键词: antioxidants; behavior test; brain injury; cell sorting; cognition disorders; confocal scanning microscopy; cytokine; enzyme linked immunosorbent assay; estrogen receptors; estrogens; gender difference; hormone regulation /control mechanism; hormone therapy; immunocytochemistry; inflammation; laboratory rat; light microscopy; neurohormones; neuroprotectants; nonhuman therapy evaluation; polymerase chain reaction; scintillation counter; sensorimotor system; trauma; western blottings

DESCRIPTION (provided by applicant): The efficacy of estrogen treatment in several injury models has been previously reported. Our own recent work has demonstrated a reduction in contusion volumes following traumatic brain injury (TBI) in female rats versus males or ovariectomized females. Although several mechanistic pathways for this neuroprotection have been explored, one that has not and is important after TBI is inflammation. TBI produces a robust inflammatory response that is both acute and chronic in duration. Several investigators using other models have reported the ability of estrogen to inhibit specific components of the inflammatory cascade. The proposed studies will assess differences between males and females after TBI with regard to post-traumatic inflammation. Four specific aims are proposed to address this issue. In specific aim 1, we will measure levels of proinflammatory cytokines and determine the cellular source of these initiators of inflammation. These studies will provide novel data on differences between males and females and in addition, by using ovariectomized females, the influence of reproductive steroids. In the second aim, we will study regional patterns of iNOS expression and determine if this response is sex and hormone-dependent. Because iNOS has been implicated in the pathogenesis of TBI, this inflammatory response to trauma requires investigation in the present setting. Specific aim 3 will assess whether estrogen's effect on the inflammatory cascade after TBI is due to antioxidant properties or receptor-mediated mechanisms. Because estrogen has been reported to effect various components of the inflammatory cascade, its effect on trauma-induced inflammatory processes requires further investigation. Results from this study will provide novel data for the potential use of neurohormones in the treatment of TBI. In the final aim, estrogen isomers or specific estrogen receptor antagonist/agonist will be administered after TBI to assess recovery of function. Taken together, these experiments will provide new data on the importance of neurohormones on structural and functional outcome after TBI. Established methods including rodent models of TBI, behavioral tests, as well as immunocytochemical and molecular approaches will be used in this proposal.

描述（由申请人提供）：雌激素治疗在几种损伤模型中的疗效先前已有报道。我们最近的研究表明，与雄性大鼠或卵巢切除的雌性大鼠相比，雌性大鼠创伤性脑损伤（TBI）后的挫伤体积减少。尽管已经探索了这种神经保护的几种机制途径，但在TBI后还没有并且很重要的一种是炎症。TBI产生强烈的炎症反应，其在持续时间上是急性和慢性的。一些研究人员使用其他模型报道了雌激素抑制炎症级联反应的特定组分的能力。拟议的研究将评估TBI后男性和女性在创伤后炎症方面的差异。为解决这一问题提出了四个具体目标。在具体目标1中，我们将测量促炎细胞因子的水平并确定这些炎症引发剂的细胞来源。这些研究将提供关于男性和女性之间差异的新数据，此外，通过使用卵巢切除女性，生殖类固醇的影响。在第二个目标中，我们将研究iNOS表达的区域模式，并确定这种反应是否是性别和性别依赖性的。由于iNOS参与了TBI的发病机制，因此需要在目前的背景下研究创伤的炎症反应。具体目标3将评估雌激素对TBI后炎症级联反应的影响是否是由于抗氧化特性或受体介导的机制。由于雌激素已被报道影响炎症级联反应的各种成分，其对创伤诱导的炎症过程的影响需要进一步研究。这项研究的结果将为神经激素在TBI治疗中的潜在用途提供新的数据。最终目的是在TBI后给予雌激素异构体或特异性雌激素受体拮抗剂/激动剂，以评估功能恢复。总之，这些实验将提供新的数据的重要性，神经激素的结构和功能的结果后，TBI。已建立的方法，包括啮齿类动物模型的TBI，行为测试，以及免疫细胞化学和分子方法将用于本提案。