CELL BIOLOGICAL STUDIES IN ALZHEIMERS DISEASE

阿尔茨海默病的细胞生物学研究

• 批准号: 2050540
• 负责人: JOHN P BLASS
• 金额: $ 48.39万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2050540
• 关键词: Alzheimer's disease; cellular pathology

The aim of this LEAD application is to test the value of examining cellular and molecular abnormalities in extra-neural tissues from patients with Alzheimer's disease (DAT). It will test whether or not reported abnormalities relate to the presence of -the clinical syndrome of DAT or certain of its subgroups (familial vs sporadic, early vs.late onset, with vs without Parkinsonism, myoclonus, depression, or early aphasia). DAT patients and disease and intact controls of comparable age and sex will all receive detailed examination including neuropsychological testing; follow-up where possible will be to autopsy. Skin cell cultures including biopsy will be meticulously standardized to ensure that DAT and control cells are studied under identical conditions including identical biological age in culture. Parameters measured in the cultures will include two related to the materials which accumulate in DAT brain: amyloid precursor protein, and materials which react with antibodies to paired helical filaments (PHF). (Recent studies by the PI and co-workers indicate that skin cells accumulate anti-PHF reactive materials when grown under specified conditions, much more in DAT cells than in controls). Other parameters to be measured have been reported abnormal in DAT calls in at least two laboratories: isoproterenol-stimulated cyclic AMP synthesis, cellular calcium homeostasis, and [U-14C]glutamine oxidation. Data will be stored in a relational data base (SIR-software) and relations among clinical and laboratory findings analyzed in detail (SAS statistical software). Dr Ronald Black, an assistant professor of Neurology, will develop methods to quantitate anti-PHF reactive materials, compare the amounts of these materials in soluble and insoluble fractions of affected and unaffected areas of DAT and control brains, and then compare their amounts in cultured DAT and control cells. He will gain expertise in clinical as well as laboratory research in dementias by participating actively in the clinical evaluations. One pilot study will examine a possible increase in anti-APP reactive materials in DAT granulocytes, and a second possible abnormalities in phosphokinase activities in cultured DAT skin cells. Future pilots will also study other potential markers. The proposed investigations will extend the PI's ongoing mechanistic studies of abnormalities in cultured DAT cells. They will test directly whether or not the abnormalities studied relate closely to the clinical syndrome of DAT or to DAT subgroups.

这个Lead应用程序的目的是测试检查 患者神经外组织中的细胞和分子异常 患有阿尔茨海默病(DAT)。它将测试是否报告 异常与DAT或-临床综合征的存在有关 其某些亚群(家族性与散发性、早发性与晚发性、 与没有帕金森氏症、肌阵挛、抑郁或早期失语的患者相比)。日期 患者和疾病以及年龄和性别相当的完整对照都将 接受详细检查，包括神经心理测试； 在可能的情况下，后续将进行尸检。皮肤细胞培养包括 活检将严格标准化，以确保DAT和控制 细胞在相同的条件下进行研究，包括相同的生物学条件 文化中的年龄。在培养中测量的参数将包括两个 与DAT脑内积聚的物质有关：淀粉样前体 蛋白质，以及与成对螺旋抗体反应的材料 长丝(PHF)。(私人侦探和同事最近的研究表明， 皮肤细胞在以下环境中生长时积累抗PHF活性物质 特定条件下，在DAT细胞中比在对照中多得多)。其他 在以下位置的DAT调用中报告了要测量的参数异常 至少两个实验室：异丙肾上腺素刺激的环状AMP合成， 细胞内钙稳态和[U-14C]谷氨酰胺氧化。数据将是 存储在关系数据库(SIR软件)中，以及它们之间的关系 详细分析临床和实验室结果(SAS统计 软件)。 神经学助理教授罗纳德·布莱克博士将开发出 方法对抗PHF活性物质进行定量，比较不同剂量的抗PHF活性物质 这些物质在受影响和不能溶解的部分中 DAT和对照大脑未受影响的区域，然后比较它们的数量 在培养的DAT细胞和对照细胞中。他将获得临床AS方面的专业知识 以及痴呆症的实验室研究，积极参与 临床评估。 一项试点研究将检查反应用程序反应性的可能增加 DAT粒细胞中的物质，以及第二种可能的异常 培养的DAT皮肤细胞中的磷酸激酶活性。未来的飞行员将 还要研究其他潜在的标记物。 拟议的调查将扩展PI正在进行的机制 培养的DAT细胞异常的研究。他们将直接测试 所研究的异常是否与临床密切相关 DAT综合征或DAT亚组。