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

黄体酮、TBI 和 CNS 修复成熟

• 批准号: 6968102
• 负责人: DONALD G. STEIN
• 金额: $ 35.38万
• 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/6968102
• 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（由申请人提供）：每年发生超过一百万例创伤性脑损伤（TBI），但目前还没有临床有效的治疗方法来预防神经元丢失和增强行为功能。对CRISP数据库（1972-2004）的检查发现，只有两个NIH赞助的赠款解决老年人TBI！显然需要的是一种安全、易于管理的药物，可以促进脑和脊髓损伤的形态和行为在整个生命周期中的恢复。目前埃默里大学正在进行一项针对中度至重度钝性头部创伤的I/II期临床试验，一种有前途的药物是神经类固醇孕酮。在我们以前的研究中，这个修订的建议是一个扩展，我们的实验室表明，短期的大鼠损伤后注射黄体酮可以减少脑水肿，增强神经元保护，并改善认知，感觉和运动功能的大鼠双侧挫伤的内侧额叶皮层。虽然孕酮被认为是有效的，足以保证临床试验，仍然有很多要了解它，及其相关的前体和代谢物，如何影响老年动物的功能和形态恢复。大部分TBI研究集中在儿童和年轻人，但它也是一个实质性的问题，老年人，谁往往是严重的脑损伤的福尔斯和事故！我们的具体目标是：（1）使用剂量-反应范例中的行为测定，我们将检查孕酮治疗对衰老和年轻成年雄性和雌性实验室大鼠的功能影响。(2)在确定孕酮减少促炎基因的表达后，我们将使用免疫细胞化学（ICC）和分子生物学技术来研究这种类固醇如何影响由基因产生的炎症蛋白的水平，以及这些物质的减少如何影响成年和老年动物TBI后的水肿和免疫细胞侵袭。(3)由于合成形式的孕酮广泛用于人类使用，并且在临床实践中经常与天然孕酮（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，MPA是一种合成分子，具有与孕酮本身不同的受体和细胞作用。