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.

血小板膜流动性（PMF）增加，通过 荧光各向异性的降低 标记膜中的1，6-二苯基-1，3，5-己三烯（DPh），鉴定了 阿尔茨海默病（AD）患者亚组具有明显的 临床特征 这种表型似乎是一个稳定的，家族性的 这种特质是在患者的家庭中垂直传播的， 老年痴呆症 对这些家庭的数据进行分离分析 表明PMF的增加是由于遗传了一个 控制至少80%变异的主要基因座 膜表型 因此，PMF轨迹似乎是一个重要的 和阿尔茨海默病临床异质性的共同遗传来源 疾病 在细胞水平上，来自超微结构和 生物化学研究表明，PMF的增加是由于 异常内膜积聚，类似光滑 内质网功能异常。 期间 在要求的授标期间，我们建议前瞻性地评估增加的 PMF作为AD的危险因素，以进一步定义细胞和 增加PMF的分子基础，并利用这些信息， 对死后脑组织的直接假设驱动的研究， 阐明AD的病理生理学。 我们的具体目标是：1. 确定PMF增加是否预示原发性 在一个由330名一级亲属组成的高风险队列中， 在进入研究时认知完整的AD患者 这项正在进行的纵向研究。 作为这项研究的一部分， 将建立细胞系，以促进未来的研究， AD的遗传风险因素。 2. 确定PMF是否 基因座位于长臂21号染色体上，其中几个基因 与AD的生物学相关的疾病之前已经被定位，或接近 据报道，19号染色体的区域赋予易患AD的可能性。 3. 确定点突变的频率和分布， APP基因的跨膜区在确诊的AD患者和 死亡时未患AD的患者。 4. 确定 PMF增加是否直接导致 内膜的流动性选择性增加， 血小板膜，或两者，使用分离的内部制剂， 和血小板外膜。 如果按照我们初步的建议 研究，观察到两种改变，膜组成 负责内部流动性增加的变化 膜也将被研究。 5. 确定分布 可溶性和膜结合形式的淀粉样前体蛋白 (APP)在血小板，并调查是否处理或 这种糖基化膜蛋白的分布在AD中改变 PMF增加的患者。 6. 研究的关系 PMF对老年斑密度的生前测定 和神经系统缠结的病人， 确认AD