SIMULATION OF BIOMOLECULES

生物分子模拟

• 批准号: 6295155
• 负责人: Martin Karplus
• 金额: $ 1.19万
• 依托单位: MELLON PITTS CORPORATION (MPC CORP)
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6295155
• 关键词: biological products; biomedical resource; computers

Increased platelet membrane fluidity (PMF), as measured by a decrease in the fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPh) in labeled membranes, identifies a subgroup of patients with Alzheimer's disease (AD) who have distinct clinical features. This phenotype appears to be a stable, familial trait that is vertically transmitted in families of patients with Alzheimer's disease. Segregation analysis of data from these families indicates that increased PMF results from the inheritance of a single major locus that controls at least 80% of the variance in this membrane phenotype. Thus, the PMF locus appears to be an important and common genetic source of clinical heterogeneity in Alzheimer's disease. At the cellular level, evidence from ultrastructural and biochemical studies suggests that increased PMF results from an accumulation of abnormal internal membranes resembling smooth endoplasmic reticulum that may be functionally abnormal. During the requested award period, we propose to prospectively evaluate increased PMF as a risk factor for AD, to further define the cellular and molecular basis for increased PMF, and to use this information to direct hypothesis-driven studies of post-mortem brain tissue aimed at elucidating the pathophysiology of AD. Our specific aims are to: 1. Determine whether increased PMF predicts the incidence of primary dementia in a high-risk cohort of 330 first-degree relatives of patients with AD who were cognitively intact at the time of entry into this ongoing longitudinal study. As part of this study, transformed cell lines will be established to facilitate future studies of putative genetic risk factors for AD. 2. Determine whether the PMF locus is located on the long arm chromosome 21, where several genes related to the biology of AD have been previously localized, or near a region of chromosome 19 reported to confer vulnerability to AD. 3. Determine the frequency and distribution of point mutations across the transmembrane region of the APP gene in patients with confirmed AD and patients who did not have AD at the time of death. 4. Determine directly whether increased PMF results form an accumulation of internal membranes, a selective increase in the fluidity of internal platelet membranes, or both, using isolated preparations of internal and external platelet membranes. If, as suggested by our preliminary studies, both alterations are observed, the membrane compositional changes responsible for the increased fluidity of the internal membranes will also be investigated. 5. Determine the distribution of the soluble and membrane-bound forms of b-amyloid precursor protein (APP) in platelets, and investigate whether the processing or distribution of this glycosylated membrane protein is altered in AD patients with increased PMF. 6. Examine the relationship of antemortem determinations of PMF to the densities of senile plaques and neurofibrillary tangles in the brains of patients who died with confirmed AD.

通过A测量的血小板膜流动性（PMF）增加 荧光各向异性的减少 标记膜中的1,6-二苯基-1,3,5-己二烯（DPH），鉴定 具有不同的阿尔茨海默氏病（AD）患者的亚组 临床特征。 这种表型似乎是一种稳定的家族性 特征是在患者家庭中垂直传播的 阿尔茨海默氏病。 这些家庭数据的隔离分析 表明PMF的增加是由单个的继承而导致的 控制这一方差的80％的主要基因座 膜表型。 因此，PMF基因座似乎很重要 和阿尔茨海默氏症临床异质性的常见遗传来源 疾病。 在细胞水平，超微结构和 生化研究表明，PMF的增加来自 异常内膜的累积相似 可能在功能异常的内质网。 在 要求颁发期限，我们建议预期评估增加 PMF作为AD的危险因素，进一步定义细胞和 增加PMF的分子基础，并将这些信息用于 尸体后脑组织的直接假设驱动的研究针对 阐明AD的病理生理。 我们的具体目的是：1。 确定增加的PMF是否预测了原发性的发生率 痴呆在330个一级亲戚的高风险队列中 AD的患者在进入时认知完好无损 这项正在进行的纵向研究。 作为这项研究的一部分，转化了 将建立细胞系以促进未来的研究 AD的推定遗传危险因素。 2。确定PMF是否 基因座位于长臂染色体21中，其中几个基因 与AD的生物学有关 染色体19区的区域据报道赋予AD脆弱性。 3。 确定点突变的频率和分布 确认的AD患者和APP基因的跨膜区域 死亡时没有AD的患者。 4。确定 直接增加PMF结果是否形成了 内膜，内部流动性的选择性增加 使用内部孤立的制剂，血小板膜或两者兼有 和外部血小板膜。 如果，正如我们的初步建议 研究，观察到两个变化，膜成分 变化导致内部流动性增加 膜也将进行研究。 5。确定分布 B-淀粉样前体蛋白的可溶性和膜结合形式 （应用程序）在血小板中，并调查处理或 该糖基化膜蛋白的分布在AD中改变了 PMF的患者增加。 6。检查 PMF对老年斑块的密度测定 和死于患者的大脑中的神经原纤维缠结 确认的广告。