Pathologic protein folding and human disease
Pathologic protein folding and human disease
批准号:
7663805
负责人:
DAVID B. TEPLOW
金额:
$153.53万
依托单位国家:
美国
项目类别:
财政年份:
2006
资助国家:
美国
项目状态:
已结题
起止时间:
2006-09-01 至 2011-07-31
中文摘要
描述(由申请人提供):病理性蛋白质折叠引起的疾病是老年人遭受的最具破坏性的疾病之一。这些疾病包括阿尔茨海默氏症、亨廷顿氏症、帕金森氏症、家族性淀粉样多神经病变和朊病毒。每一种疾病都是致命的,会导致认知能力和身体衰退。每一种都与导致蛋白质功能障碍的蛋白质异常折叠有关。功能障碍既来自蛋白质单体结构的内在改变,也来自蛋白质的自结合(聚集)。后一种现象经常发生在痴呆疾病,其中阿尔茨海默病(AD)是最常见的。在阿尔茨海默病中,淀粉样β蛋白(Abeta)自结合形成寡聚结构,在血浆和脑脊液中循环。随着疾病的进展,大脑中发现的Aa沉积物的数量和大小都在增加。这些沉积物被称为“淀粉样斑块”,含有纤维状的β聚合物。大多数阿尔茨海默病病例与同源结构基因的突变无关。这就提出了为什么会发生病理折叠和Abeta组装的问题,以及为什么65岁以后疾病发病率会急剧上升。在这些方面,阿尔茨海默病并不是唯一的,因为其他痴呆疾病也属于“衰老疾病”。本项目项目(Program)解决的一般问题领域是病理性蛋白质折叠和组装,如Abeta。我们假设β的构象变化导致寡聚化,而由此产生的寡聚体组装是导致AD的近似神经毒素。为了验证这一假设,我们提出了两个长期的具体目标:
英文摘要
DESCRIPTION (provided by applicant): Diseases caused by pathologic protein folding are among the most devastating suffered by the aged. These diseases include Alzheimer's, Huntington's, Parkinson's, familial amyloid polyneuropathy, and prion. Each is a fatal disorder causing progressive cognitive and physical decline. Each is linked to aberrant folding of proteins that results in protein dysfunction. Dysfunction comes both from intrinsic changes in protein monomer structure and protein self-association (aggregation). The latter phenomenon occurs frequently in the dementing illnesses, of which Alzheimer's disease (AD) is the most common. In AD, the amyloid beta-protein (Abeta) self-associates to form oligomeric structures that circulate in plasma and cerebrospinal fluid. As the disease progresses, deposits of Aa are found in increasing number and size in the brain. These deposits, termed "amyloid plaques," contain fibrillar polymers of Abeta. Most cases of AD are not linked to mutations in the cognate structural gene for Abeta. This raises the questions of why pathologic folding and assembly of Abeta occur and why disease incidence increases so sharply after the age of 65. AD is not unique in these respects, as other dementing illnesses also are "diseases of aging." The general problem area addressed by this Program Project (Program) is pathologic protein folding and assembly, as exemplified by Abeta. We hypothesize that conformational changes in Abeta lead to oligomerization and that the resulting oligomeric assemblies are the proximate neurotoxins causing AD. To test this hypothesis, we propose two long-term specific aims:
1. To understand, at the most fundamental biophysical and cellular levels, how aberrant folding of proteins produces human disease.
2. To translate this knowledge into the design and implementation of new therapeutic agents.
To accomplish these aims, five principal investigators at four different American universities have joined together to create a tightly-integrated program comprising two administrative cores and five projects. Our long-term strategy seeks first to establish a cohesive and productive research enterprise focused on AD and Abeta. We make this choice because AD is the most common cause of late-life dementia, its incidence is predicted to increase significantly, and Abeta assembly has proven to be archetypal for amyloid proteins. This last point is important, because the Program is designed to advance our understanding of AD and provide new technologies applicable in studies of folding and assembly of other amyloid and non-amyloid proteins. We thus envision the significance of the Program extending beyond solely AD.
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会议论文
Physical Biochemistry and Biology of Amyloid Beta-Protein
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批准号:8332301
-
项目类别:
-
资助金额:$31.57万
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财政年份:2011
-
负责人:DAVID B. TEPLOW
-
依托单位:
Physical Biochemistry and Biology of Amyloid Beta-Protein
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批准号:8850772
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项目类别:
-
资助金额:$30.62万
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财政年份:2011
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负责人:DAVID B. TEPLOW
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依托单位:
Physical Biochemistry and Biology of Amyloid Beta-Protein
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批准号:8531820
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项目类别:
-
资助金额:$29.83万
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财政年份:2011
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负责人:DAVID B. TEPLOW
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依托单位:
Physical Biochemistry and Biology of Amyloid Beta-Protein
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批准号:8222749
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项目类别:
-
资助金额:$31.57万
-
财政年份:2011
-
负责人:DAVID B. TEPLOW
-
依托单位:
Physical Biochemistry and Biology of Amyloid Beta-Protein
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批准号:8722423
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项目类别:
-
资助金额:$31.57万
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财政年份:2011
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负责人:DAVID B. TEPLOW
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依托单位:
SIMULATION OF AMYLOID BETA-PROTEIN FOLDING AND ASSEMBLY
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批准号:7724408
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项目类别:
-
资助金额:$0.26万
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财政年份:2008
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负责人:DAVID B. TEPLOW
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依托单位:
SIMULATION OF AMYLOID BETA-PROTEIN FOLDING AND ASSEMBLY
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批准号:7627780
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项目类别:
-
资助金额:$2.01万
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财政年份:2007
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负责人:DAVID B. TEPLOW
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依托单位:
Pathologic protein folding and human disease
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批准号:7279127
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项目类别:
-
资助金额:$149.23万
-
财政年份:2006
-
负责人:DAVID B. TEPLOW
-
依托单位:
Pathologic protein folding and human disease
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批准号:7080008
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项目类别:
-
资助金额:$154.72万
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财政年份:2006
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负责人:DAVID B. TEPLOW
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依托单位:
PHYSICAL BIOCHEMISTRY AND BIOLOGY OF AMYLOID B-PROTEIN
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批准号:7112180
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项目类别:
-
资助金额:$19.74万
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财政年份:2006
-
负责人:DAVID B. TEPLOW
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依托单位:
Pathologic protein folding and human disease
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批准号:7469486
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项目类别:
-
资助金额:$150.19万
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财政年份:2006
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负责人:DAVID B. TEPLOW
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依托单位:
PROTEIN CHEMISTRY CORE
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批准号:7112179
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项目类别:
-
资助金额:$26.67万
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财政年份:2006
-
负责人:DAVID B. TEPLOW
-
依托单位:
Pathologic protein folding and human disease
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批准号:7903270
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项目类别:
-
资助金额:$155.27万
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财政年份:2006
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负责人:DAVID B. TEPLOW
-
依托单位:
PROCISE CLC SEQUENCING SYST: MULTIPLE SCLEROSIS, EXPERIMENTAL AUTOIMMUNE ENCEPHA
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批准号:6973352
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项目类别:
-
资助金额:$5.53万
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财政年份:2004
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负责人:DAVID B. TEPLOW
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依托单位:
PROCISE CLC SEQUENCING SYST: ALZHEIMER'S DISEASE
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批准号:6973351
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项目类别:
-
资助金额:$11.06万
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财政年份:2004
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负责人:DAVID B. TEPLOW
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依托单位:
PROCISE cLC Sequencing System 2 Cart w/PC
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批准号:6730937
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项目类别:
-
资助金额:$18.44万
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财政年份:2004
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负责人:DAVID B. TEPLOW
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依托单位:
PROCISE CLC SEQUENCING SYST: OSTEOPOROSIS
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批准号:6973353
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项目类别:
-
资助金额:$0.92万
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财政年份:2004
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负责人:DAVID B. TEPLOW
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依托单位:
PROCISE CLC SEQUENCING SYST: PARKINSON'S DISEASE
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批准号:6973354
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项目类别:
-
资助金额:$0.92万
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财政年份:2004
-
负责人:DAVID B. TEPLOW
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依托单位:
Formation and Function of Prefibrillar ABeta Assemblies
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批准号:7125471
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项目类别:
-
资助金额:$46.61万
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财政年份:2003
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负责人:DAVID B. TEPLOW
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依托单位:
Formation and Function of Prefibrillar ABeta Assemblies
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批准号:7122656
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项目类别:
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资助金额:$46.37万
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财政年份:2003
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负责人:DAVID B. TEPLOW
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依托单位:
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