PROGESTERONE, TBI AND CNS REPAIR IN MATURE & AGED RATS.

黄体酮、TBI 和 CNS 修复成熟

• 批准号: 7112928
• 负责人: DONALD G. STEIN
• 金额: $ 34.55万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112928
• 关键词: age difference; animal old age; behavior test; behavioral /social science research tag; brain edema; brain injury; dosage; frontal lobe /cortex; functional ability; gel mobility shift assay; hormone receptor; hormone regulation /control mechanism; hormone therapy; immunocytochemistry; juvenile animal; laboratory rat; nervous system regeneration; neural plasticity; neuroprotectants; nonhuman therapy evaluation; progesterone; spinal cord injury; trauma; western blottings

DESCRIPTION (provided by applicant): Over a million cases of traumatic brain injury (TBI) occur each year, yet at present there are no clinically effective treatments to prevent neuronal loss and enhance behavioral functions. An examination of the CRISP database (1972-2004) found only two NIH-sponsored grants addressing TBI in the elderly! What is clearly needed is a safe, easy-to-administer agent that can promote morphological and behavioral recovery in brain and spinal cord injuries across the life span. A promising agent currently under test at Emory University in a phase I/II clinical trial for moderate to severe blunt head trauma, is the neurosteroid progesterone. In our previous research, of which this revised proposal is an extension, our laboratory showed that a short course of post-injury progesterone injections in rats could reduce cerebral edema, enhance neuronal sparing, and improve cognitive, sensory and motor functions in rats with bilateral contusions of the medial frontal cortex. Although progesterone was deemed effective enough to warrant clinical testing, there is still much to learn about how it, and its related precursors and metabolites, affect functional and morphological recovery in old animals. The bulk of TBI research focuses on children and young adults, but it is also a substantive issue for the elderly, who are often seriously brain-injured by falls and accidents! Our specific aims here are: (1) Using behavioral assays in a dose-response paradigm, we will examine the functional effects of progesterone treatments in senescent and young adult male and female laboratory rats. (2) Having determined that progesterone reduces the expression of pro-inflammatory genes, we will use immunocytochemical (ICC) and molecular biological techniques to investigate how this steroid affects the level of inflammatory proteins made by the genes, and how the reduction of these substances affects edema and immune cell invasion after TBI in both adult and old animals. (3) Because synthetic forms of progesterone are widely available for human use and are often interchanged for natural progesterone (nPROG) in clinical practice, we will compare the effectiveness and mechanisms of action of nPROG with medroxyprogesterone acetate (MPA), a synthetic molecule which has receptor and cellular actions that can be different from those of progesterone itself.

描述（申请人提供）：每年发生超过百万例创伤性脑损伤（TBI），但目前临床上尚无有效的治疗方法来预防神经元损失和增强行为功能。对 CRISP 数据库（1972-2004）的检查发现，只有两项 NIH 赞助的拨款用于解决老年人 TBI 问题！显然需要的是一种安全、易于施用的药物，可以促进大脑和脊髓损伤在整个生命周期的形态和行为恢复。目前埃默里大学正在针对中度至重度钝性头部创伤进行 I/II 期临床试验，测试一种有前途的药物，那就是神经类固醇黄体酮。在我们之前的研究中，我们的实验室表明，对大鼠进行短期损伤后黄体酮注射可以减轻脑水肿，增强神经元保护，并改善双侧大脑损伤大鼠的认知、感觉和运动功能，本次修订后的提案是该研究的延伸。内侧额叶皮质挫伤。尽管黄体酮被认为足够有效，足以进行临床测试，但关于它及其相关前体和代谢物如何影响老年动物的功能和形态恢复，仍有很多东西需要了解。 TBI研究的大部分集中在儿童和年轻人身上，但对于老年人来说，这也是一个实质性问题，因为老年人经常因跌倒和事故而遭受严重脑损伤！我们的具体目标是：（1）在剂量反应范式中使用行为测定，我们将检查黄体酮治疗对衰老和年轻成年雄性和雌性实验大鼠的功能影响。 （2）确定黄体酮会降低促炎基因的表达，我们将利用免疫细胞化学（ICC）和分子生物学技术来研究这种类固醇如何影响该基因产生的炎症蛋白的水平，以及这些物质的减少是如何进行的影响成年和老年动物 TBI 后的水肿和免疫细胞侵袭。 (3) 由于合成形式的黄体酮广泛供人类使用，并且在临床实践中经常与天然黄体酮 (nPROG) 互换，因此我们将比较 nPROG 与醋酸甲羟孕酮 (MPA) 的有效性和作用机制，醋酸甲羟孕酮 (MPA) 是一种合成分子，具有与黄体酮本身不同的受体和细胞作用。