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ALZHEIMERS DISEASE AND AMYLOID PROTEINS

ALZHEIMERS DISEASE AND AMYLOID PROTEINS
阿尔茨海默病和淀粉样蛋白
批准号:
2052181
负责人:
BLAS FRANGIONE
金额:
$78.37万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1992
资助国家:
美国
项目状态:
已结题
起止时间:
1992-09-30 至 1999-08-31

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中文摘要
翻译
阿尔茨海默病(AD)和神经退行性疾病的淀粉样蛋白 人类的相关疾病是由大细胞膜的蛋白分解引起的 前体蛋白(APP)。我们的核心利益在于明显的联系 神经退行性变和淀粉样蛋白之间的关系及其测定 启动和维持淀粉样蛋白形成的因素。我们的工作 假设是遗传变异(S)和/或某种异常 阿尔茨海默病APP病因的翻译后修饰 结构/构象修饰。这样改变的蛋白质可能 强烈抵抗蛋白质分解攻击,和/或它们可能会经历异常 退化。这些抗蛋白酶的裂解肽具有很强的 聚集的倾向可能与其他细胞或血清成分结合,因此 促进聚合和纤维的形成。最有可能的 那么,阿尔茨海默病的病理级联是:淀粉样蛋白沉积、神经原纤维 缠结形成和神经元死亡。更好的生物化学理解 在人类和动物模型中的这种病理过程将有助于 治疗性干预。 这个铅奖申请的具体目标是:i)生化 淀粉样蛋白和前肌样蛋白的免疫组织化学特征 家族性和散发性AD的损害与遗传性脑出血 荷兰型淀粉样变性(HCHWA-D)(项目1)。二)机制: 淀粉样蛋白形成:研究已知突变对淀粉样蛋白形成的影响 应用APP基因和淀粉样蛋白相关蛋白对纤维形成的影响 合成肽和由Alternate产生的16-19 kDa APP片段 退化途径。抑制纤维形成的治疗方法 将在转基因小鼠身上进行评估(项目2)。三)研究 APP的替代加工和生物性能(项目3)..四) 早发性痴呆家系APP基因突变的检测 FAD的发病与转基因小鼠动物模型的构建 携带具有不同突变的人类APP基因(项目4)。v) 一种新型家族性脑血管病的特征 与其他疾病无关的英国痴呆患者的淀粉样变性 已知的类型。
英文摘要
The amyloid of neurodegenerative diseases like Alzheimer's Disease (AD) and related disorders in man is derived by proteolysis of a large membrane precursor protein (APP). Our central interest lies in the apparent link between neurodegeneration and amyloidogenic proteins, and the determination of the factors that initiate and perpetuate amyloid formation. Our working hypothesis is that genetic variant(s) and/or some aberrant posttranslational modification of Alzheimer's APP causes structural/conformational modifications. Proteins thus altered may strongly resist proteolytic attack, and/or they may undergo abnormal degradation. These protease-resistant cleavage peptides with strong tendency to aggregate may bind to other cellular or serum components, thus facilitating polymerization and fibril formation. The most likely pathological cascade for AD, then, is: amyloid deposition, neurofibrillary tangle formation and neuronal death. Better biochemical understanding of this pathological process in human and in animal models would facilitate therapeutic intervention. The Specific Aims of this LEAD award application are: i) The biochemical and immunohistochemical characterization of amyloid proteins and preamyloid lesions from familial and sporadic AD and Hereditary Cerebral Hemorrhage with Amyloidosis, Dutch type (HCHWA-D) (PROJECT 1). ii) The mechanisms of amyloid formation: to study the influence of the known mutations of the APP gene and amyloid associated proteins on fibril formation using synthetic peptides and the 16-19 kDa APP fragments produced by alternative degradation pathways. Therapeutic approaches to inhibit fibrillogenesis will be evaluated in transgenic mice (PROJECT 2). iii) The study of the alternative processing and biological properties of APP (PROJECT 3).. iv) The identification of mutations of the APP gene in families with early onset FAD and the construction of an animal model: transgenic mice harboring the human APP gene with the different mutations (PROJECT 4). v) The characterization of a novel type of familial cerebrovascular amyloidosis with dementia in British patients that is not related to other known types.
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THE BIOCHEMISTRY OF BRAIN AMYLOIDS AND PREAMYLOID LESIONS
THE BIOCHEMISTRY OF BRAIN AMYLOIDS AND PREAMYLOID LESIONS
ALZHEIMERS DISEASE AND AMYLOID PROTEINS
  • 批准号:
    2052182
  • 项目类别:
  • 资助金额:
    $66.24万
  • 财政年份:
    1992
  • 负责人:
    BLAS FRANGIONE
  • 依托单位:
ALZHEIMER'S DISEASE AND AMYLOID PROTEINS
  • 批准号:
    3478957
  • 项目类别:
  • 资助金额:
    $72.21万
  • 财政年份:
    1992
  • 负责人:
    BLAS FRANGIONE
  • 依托单位:
海外基金