ALZHEIMERS DISEASE AND AMYLOID PROTEINS
ALZHEIMERS DISEASE AND AMYLOID PROTEINS
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
中文摘要
神经退行性疾病如阿尔茨海默病(AD)的淀粉样蛋白,
人类的相关疾病是由大膜的蛋白水解引起的,
前体蛋白(APP)。 我们的主要兴趣在于
神经变性和淀粉样蛋白之间的联系,
淀粉样蛋白形成的起始和持续因素。 我们的工作
假设是遗传变异和/或某些异常
阿尔茨海默氏症APP的翻译后修饰导致
结构/构象修饰。 这样改变的蛋白质可能
强烈抵抗蛋白水解攻击,和/或它们可能经历异常
降解 这些蛋白酶抗性切割肽具有强的
聚集的倾向可能与其他细胞或血清成分结合,因此
促进聚合和原纤维形成。 最可能的
那么,AD的病理级联反应是:淀粉样蛋白沉积,神经胶质细胞增生,
缠结形成和神经元死亡。 更好地了解生物化学
在人类和动物模型中的这种病理过程将促进
治疗干预
该LEAD奖申请的具体目标是:i)生物化学
淀粉样蛋白和类淀粉样蛋白的免疫组织化学特征
家族性和散发性AD与遗传性脑出血的病变
淀粉样变性,荷兰型(HCHWA-D)(项目1)。 (二)机制
淀粉样蛋白的形成:研究已知的淀粉样蛋白基因突变对淀粉样蛋白形成的影响。
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16-19 kDa的APP片段,
降解途径 抑制纤维形成的治疗方法
将在转基因小鼠中进行评价(项目2)。 (三)研究
APP的替代加工和生物学特性(项目3)。 iv)第四条
早发冠心病家系APP基因突变的检测
FAD发病及转基因小鼠动物模型的建立
携带具有不同突变的人APP基因(项目4)。 五)
一种新的家族性脑血管病的特征
在英国患者中,淀粉样变性伴痴呆与其他
已知类型
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
THE BIOCHEMISTRY OF BRAIN AMYLOIDS AND PREAMYLOID LESIONS
-
批准号:6098460
-
项目类别:
-
资助金额:$13.14万
-
财政年份:1998
-
负责人:BLAS FRANGIONE
-
依托单位:
THE BIOCHEMISTRY OF BRAIN AMYLOIDS AND PREAMYLOID LESIONS
-
批准号:6234426
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项目类别:
-
资助金额:$12.74万
-
财政年份:1997
-
负责人:BLAS FRANGIONE
-
依托单位:
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:
ALZHEIMERS DISEASE AND AMYLOID PROTEINS
-
批准号:2001452
-
项目类别:
-
资助金额:$68.1万
-
财政年份:1992
-
负责人:BLAS FRANGIONE
-
依托单位:
ALZHEIMERS DISEASE AND AMYLOID PROTEINS
-
批准号:2769318
-
项目类别:
-
资助金额:$65.7万
-
财政年份:1992
-
负责人:BLAS FRANGIONE
-
依托单位:
ALZHEIMERS DISEASE AND AMYLOID PROTEINS
-
批准号:2516949
-
项目类别:
-
资助金额:$63.68万
-
财政年份:1992
-
负责人:BLAS FRANGIONE
-
依托单位:
ALZHEIMER'S DISEASE AND AMYLOID PROTEINS
-
批准号:3478958
-
项目类别:
-
资助金额:$79.56万
-
财政年份:1992
-
负责人:BLAS FRANGIONE
-
依托单位:
BIOCHEMISTRY OF LEWY BODIES AND GELSOLIN AMYLOID
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批准号:3417343
-
项目类别:
-
资助金额:$23.81万
-
财政年份:1991
-
负责人:BLAS FRANGIONE
-
依托单位:
BIOCHEMISTRY OF LEWY BODIES AND GELSOLIN AMYLOID
-
批准号:2268418
-
项目类别:
-
资助金额:$24.75万
-
财政年份:1991
-
负责人:BLAS FRANGIONE
-
依托单位:
BIOCHEMISTRY OF LEWY BODIES AND GELSOLIN AMYLOID
-
批准号:3417342
-
项目类别:
-
资助金额:$21.49万
-
财政年份:1991
-
负责人:BLAS FRANGIONE
-
依托单位:
BIOCHEMISTRY OF LEWY BODIES AND GELSOLIN AMYLOID
-
批准号:3417341
-
项目类别:
-
资助金额:$21.3万
-
财政年份:1991
-
负责人:BLAS FRANGIONE
-
依托单位:
AMYLOID ANGIOPATHY EARLY PLAQUES AND AGING
-
批准号:2516922
-
项目类别:
-
资助金额:$25.08万
-
财政年份:1990
-
负责人:BLAS FRANGIONE
-
依托单位:
AMYLOID ANGIOPATHY EARLY PLAQUES AND AGING
-
批准号:2050362
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项目类别:
-
资助金额:$24.26万
-
财政年份:1990
-
负责人:BLAS FRANGIONE
-
依托单位:
AMYLOID ANGIOPATHY EARLY PLAQUES AND AGING
-
批准号:2769299
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项目类别:
-
资助金额:$25.92万
-
财政年份:1990
-
负责人:BLAS FRANGIONE
-
依托单位:
AMYLOID ANGIOPATHY, EARLY PLAQUES, AND AGING
-
批准号:2050360
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项目类别:
-
资助金额:$23.01万
-
财政年份:1990
-
负责人:BLAS FRANGIONE
-
依托单位:
AMYLOID ANGIOPATHY, EARLY PLAQUES, AND AGING
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批准号:3120458
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项目类别:
-
资助金额:$18.8万
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财政年份:1990
-
负责人:BLAS FRANGIONE
-
依托单位:
AMYLOID ANGIOPATHY, EARLY PLAQUES & AGING
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批准号:6371745
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项目类别:
-
资助金额:$43.37万
-
财政年份:1990
-
负责人:BLAS FRANGIONE
-
依托单位:
AMYLOID ANGIOPATHY, EARLY PLAQUES, AND AGING
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批准号:3120460
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项目类别:
-
资助金额:$20.77万
-
财政年份:1990
-
负责人:BLAS FRANGIONE
-
依托单位:
AMYLOID ANGIOPATHY EARLY PLAQUES AND AGING
-
批准号:6055364
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项目类别:
-
资助金额:$26.8万
-
财政年份:1990
-
负责人:BLAS FRANGIONE
-
依托单位:
海外基金