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

黄体酮、TBI 和 CNS 修复成熟

• 批准号: 7464300
• 负责人: DONALD G. STEIN
• 金额: $ 6.33万
• 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/7464300
• 关键词: Accidents; Address; Adult; Affect; Aftercare; Age; Aging-Related Process; Animal Model; Animals; Apoptosis; Area; Behavioral; Behavioral Assay; Bilateral; Biological; Brain; Brain Injuries; Cause of Death; Cells; Centers for Disease Control and Prevention (U.S.); Cerebral Edema; Cerebrum; Child; Clinical; Clinical Trials; Cognitive; Complex; Computer Retrieval of Information on Scientific Projects Database; Contusions; Craniocerebral Trauma; Data; Databases; Death Rate; Development; Distal; Dose; Drug Kinetics; Edema; Elderly; Environment; Epidemiology; Estrogens; Evaluation; Face; Female; Funding; Genes; Grant; Health; Hormonal; Hormone replacement therapy; Hormones; Human; Immune; Immune response; Impaired cognition; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; International; Intramuscular; Laboratories; Laboratory Animals; Laboratory Rat; Lead; Learning; Lesion; Life; Light; Literature; Longevity; MFC; Measures; Medial; Mediating; Medroxyprogesterone; Medroxyprogesterone 17-Acetate; Methylprednisolone; Modeling; Molecular; Morbidity - disease rate; Motor; Natural regeneration; Necrosis; Neuroglia; Neurons; Numbers; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physiological; Play; Population; Principal Investigator; Progesterone; Progesterone Receptors; Progestins; Property; Proteins; Rate; Rattus; Reaction; Recovery; Recovery of Function; Regulation; Reporting; Request for Applications; Research; Research Personnel; Review Literature; Risk; Role; Safety; Secondary to; Sensory; Sex Characteristics; Spinal cord injury; Steroids; Stroke; Structure-Activity Relationship; Synthetic Progestogens; TBI Patients; Techniques; Testing; Therapeutic Intervention; Time; Trauma; Traumatic Brain Injury; Treatment outcome; United States; United States National Institutes of Health; Universities; Update; Work; age group; aged; aging brain; base; brain tissue; clinically relevant; experience; falls; frontal lobe; functional outcomes; improved; injured; juvenile animal; male; mature animal; mortality; neuron loss; older patient; prevent; programs; receptor; repaired; research clinical testing; response; response to injury; senescence; sex; treatment duration; young adult

Over a million cases of traumatic brain injury (TBI) occur each year, yet at present there are no clinically ef- fective 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 pre- vious 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 im- prove 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 treat- ments 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 effective- ness 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.

每年发生超过一百万例创伤性脑损伤（TBI），但目前尚无临床疗效。 有效的治疗，以防止神经元损失和增强行为功能。对CRISP的审查 数据库（1972-2004）发现只有两个NIH赞助的赠款解决老年人TBI！显然是 需要一种安全、易于给药的药物， 和脊髓损伤。一种很有前途的代理人目前正在埃默里大学进行测试， I/II期临床试验，用于中度至重度钝性头部创伤，是神经甾体孕酮。在我们的预- 我们的实验室表明，一个短期的研究，其中这个修订后的建议是一个扩展， 大鼠损伤后注射孕酮可减轻脑水肿，增强神经元保护， 证明认知，感觉和运动功能的大鼠双侧挫伤的内侧额叶皮层。 虽然黄体酮被认为是有效的，足以保证临床试验，仍然有很多东西要学习 关于它及其相关的前体和代谢物如何影响老年人的功能和形态恢复， 动物大部分TBI研究集中在儿童和年轻人身上，但这也是一个实质性问题， 老年人，他们经常因福尔斯跌倒和意外而严重脑损伤！我们的具体目标是：（1）使用 在剂量反应模式的行为测定，我们将检查孕酮治疗的功能作用， 在衰老和年轻成年雄性和雌性实验室大鼠中的作用。(2)在确定孕酮 减少促炎基因的表达，我们将使用免疫细胞化学（ICC）和分子生物学技术， 生物技术来研究这种类固醇如何影响炎症蛋白的水平， 基因，以及这些物质的减少如何影响TBI后的水肿和免疫细胞侵袭， 成年和老年动物(3)由于合成形式的孕酮广泛用于人类使用， 在临床实践中，天然孕酮（nPROG）经常互换，我们将比较有效的- nPROG与合成分子醋酸甲羟孕酮（MPA）的作用性质和机制 其受体和细胞作用可能与孕酮本身不同。