THERAEUTIC POTENTIAL-NEUROTROPHINS/ALZHEIMER'S DISEASE

治疗潜力 - 神经营养素/阿尔茨海默病

• 批准号: 3091344
• 负责人: FRANZ F HEFTI
• 金额: $ 39.94万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3091344
• 关键词: Alzheimer's disease; brain disorder chemotherapy; growth factor; neural degeneration; neurotrophic factors

Alzheimer's disease (AD) is associated with degenerative changes and loss of various populations of neurons in the brain. Since neurotrophic factors regulate neuronal survival and maintenance of function, such factors may provide avenues for the development of effective treatment for AD. By preventing or attenuating neuronal degeneration, neurotrophic factors may slow down or stop the progression of the disease and associated cognitive disturbances. Based on its ability to prevent degenerative changes of cholinergic neurons induced by experimental lesions in rats and monkeys, nerve growth factor (NGF) is presently under consideration as experimental treatment for AD. One specific aim of this application, related to NGF's long-term effects and the feasibility of slow-releasing implants, will provide additional information valuable for clinical use of NGF. However, the value of NGF in the treatment of AD is limited by its specificity for forebrain cholinergic neurons. The recent discovery of homologs of NGF, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), established the family of neurotrophins. These neurotrophins affect a variety of peripheral and central neurons and their effects overlap for some neuronal populations but differ for others. Recent findings, which provide the basis for this application, indicate that posttranslational modifications of the neurotrophins influence their biological activities and their specificity to act on subsets of neuronal populations. Therefore, it is proposed to prepare modified molecular forms of the neurotrophins either by recombinant expression or by specific protease treatment. Biological effects of these modified neurotrophins will then be characterized initially in neurotrophin receptor assays and in cell culture assays.Biologically active modified neurotrophins selected by the in vitro assays will then be tested in vivo in rat brain lesion models mimicking selective degenerative changes occurring in AD brains. These modified neurotrophins will be tested for their ability to counteract molecular, morphological, and behavioral deficits induced by the experimental lesions. Additional studies, using immunohistochemistry and retrograde transport methodologies, aim at identifying previously unknown neurotrophin-responsive cell populations. In summary, this program project aims at identifying modified neurotrophins able to specifically affect survival and function of neuronal populations degenerating in Alzheimer's disease. It is hoped that the studies will lead to the discovery of modified neurotrophins with either restricted or broadened biological specificity when compared with their natural counterparts and in the identification of molecules most promising for further development as therapeutics in Alzheimer's disease. The program project joins established academic and industrial scientists with a record of previous collaboration in the pharmacological exploitation of neurotrophic factors for developing effective treatment for AD and cognitive diseases.

阿尔茨海默病（AD）与退行性变化相关， 大脑中各种神经元群体的丧失。 由于神经营养 调节神经元存活和功能维持的因素，如 这些因素可能为开发有效的治疗方法提供途径 对于AD。 通过预防或减弱神经元变性，神经营养 这些因素可能会减缓或阻止疾病的进展， 相关的认知障碍 基于其预防能力 实验性胆碱能神经元退行性改变 在大鼠和猴子的病变中，神经生长因子（NGF）目前正在 考虑作为AD的实验性治疗。 其中一个具体目标是 应用，涉及神经生长因子的长期影响和可行性， 缓释植入物，将提供额外的信息， NGF的临床应用 然而，NGF在AD治疗中的价值 由于其对前脑胆碱能神经元的特异性， 的 最近发现的脑源性神经营养因子NGF的同源物 （BDNF）和神经营养因子-3（NT-3），建立了 神经营养素 这些神经营养因子影响多种外周和 中枢神经元和它们的作用对于某些神经元群体是重叠的 但对其他人不同。 最近的调查结果，为这一点提供了依据 应用程序，表明翻译后修饰的 神经营养因子影响它们的生物活性和特异性 作用于神经元群的子集。 因此提出 制备神经营养素的修饰分子形式， 重组表达或通过特异性蛋白酶处理。 生物 这些修饰的神经营养因子的作用将被表征 最初在神经营养素受体测定和细胞培养中 生物活性修饰的神经营养素选择的研究 然后在大鼠脑损伤模型中进行体内试验 模拟AD大脑中发生的选择性退行性变化。 这些 经过修饰的神经营养素将被测试其抵消 分子，形态和行为缺陷诱导的 实验性损伤 其他研究，使用免疫组织化学和 逆行运输方法，旨在确定以前未知的 神经营养素反应细胞群。 总之，该方案 该项目旨在鉴定能够特异性地 影响神经元群体的存活和功能， 老年痴呆症 希望这些研究将导致 发现修饰的神经营养因子， 与天然对应物相比， 在鉴定最有希望用于进一步研究的分子方面， 作为阿尔茨海默病的治疗方法。 该计划项目 加入了学术界和工业界的科学家， 以前在药理学开发方面的合作 神经营养因子用于开发AD的有效治疗， 认知疾病