| 项目编号: | 1703237
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| 项目名称: | Aggregation, Inhibition, Degradation: The Cystatin C-Beta-Amyloid-Cathepsin B System |
| 作者: | Regina Murphy
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| 承担单位: | University of Wisconsin-Madison
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| 批准年: | 2017
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| 开始日期: | 2017-09-01
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| 结束日期: | 2020-08-31
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| 资助金额: | 332952
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| 资助来源: | US-NSF
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| 项目类别: | Standard Grant
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| 国家: | US
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| 语种: | 英语
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| 特色学科分类: | Engineering - Chemical, Bioengineering, Environmental, and Transport Systems
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| 英文关键词: | beta-amyloid
; cystatin c
; cathepsin b
; ba
; degradation
; protein
; interaction
; amyloid fibril
; project
; binding
; aggregation
; disease
; clumping
; amyloid
; protein aggregation
; beta-amyloid aggregation
; effective treatment strategy
; research opportunity
; amyloid regulatory network
; protein clumping
; beta-amyloid interaction
; cerebral amyloid angiopathy
; fibrillar morphology
; fibril formation
; nontoxic fragment
; cross-beta-sheet structure
; alzheimer
; individual amyloidogenic protein
; complex biological milieu
; diseased brain cell
; much research
; amyloid deposit
; abnormal clumping
; brain protein
; cerebrospinal fluid
; mathematical model
; unknown biological function
|
| 英文摘要: | Degenerative neurological disorders such as Alzheimer's or Parkinson's disease are caused by abnormal clumping of proteins into deposits called "amyloid". Amyloid can be prevented by enzymes that chop up the protein into nontoxic fragments, or by molecules that attach to the protein and prevent clumping. In this project, three brain proteins will be studied: (1) beta-amyloid (BA), the protein that forms deposits related to Alzheimer's disease, (2) cathepsin B, an enzyme that chops up BA, and (3) cystatin C, which can form amyloid deposits, prevents cathepsin B from degrading BA, and attaches to BA and prevents clumping. The interactions among these three proteins will be explored, providing new knowledge on protein clumping and degradation in healthy and diseased brain cells, and potentially providing some clues as to more effective treatment strategies for these diseases. Research opportunities will be provided to students from underrepresented groups, and an undergraduate engineering text will be revised to incorporate more examples related to protein folding diseases.
Amyloid fibrils are protein aggregates that share physicochemical properties such as cross-beta-sheet structure and fibrillar morphology. Much research has focused on aggregation of individual amyloidogenic proteins because of their importance in neurodegenerative disorders. However, protein aggregation occurs not in isolation but in a complex biological milieu of competing interactions. The triad of cystatin C, beta-amyloid, and cathepsin B constitute a network in which protein aggregation, binding, and degradation are intertwined. Cystatin C is a constituent of cerebrospinal fluid, where it serves as an inhibitor of proteases such as cathepsin B. Cystatin C amyloid deposits are found in patients with cerebral amyloid angiopathy. Beta-amyloid is a peptide of unknown biological function that aggregates into amyloid fibrils in Alzheimer's disease. Cathepsin B degrades beta-amyloid but is inhibited by cystatin C. Furthermore, binding of cystatin C to beta-amyloid inhibits beta-amyloid fibrillogenesis. Thus, cystatin C has two opposing roles: sequestering beta-amyloid and preventing fibril formation, while inhibiting cathepsin B-mediated proteolysis of beta-amyloid. The objectives of this project are to (1) characterize the structure and formation of cystatin C dimers, oligomers, and fibrils, (2) measure the effect of cystatin C on beta-amyloid aggregation, and (3) determine the role of cystatin C- beta-amyloid interactions in regulation of cathepsin B proteolytic activity. The experimental data will be used to build a mathematical model of an "amyloid regulatory network". Identification of such a network, and exploration of its interactions, will open up new lines of inquiry in protein misfolding, aggregation, and degradation in healthy and diseased tissues. |
| 资源类型: | 项目
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| 标识符: | http://119.78.100.158/handle/2HF3EXSE/88806
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| Appears in Collections: | 全球变化的国际研究计划
科学计划与规划
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| Recommended Citation: | |
Regina Murphy. Aggregation, Inhibition, Degradation: The Cystatin C-Beta-Amyloid-Cathepsin B System. 2017-01-01.
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