CAREER: Computational studies of the structure and biological activity of amyloid forming peptides
职业:淀粉样蛋白形成肽的结构和生物活性的计算研究
基本信息
- 批准号:0952624
- 负责人:
- 金额:$ 40万
- 依托单位:
- 依托单位国家:美国
- 项目类别:Continuing Grant
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-08-01 至 2016-07-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
0952624ZhengAmyloid peptides have a strong membrane associated ability that can induce cytotoxicity to neurons by altering membrane integrity and permeability. Accumulating evidences suggest that (i) soluble, low molecular weight amyloid oligomers are major toxic species and (ii) the cytotoxicity leading to the cell death could be mediated by direct interactions between amyloid oligomers and cell membrane. However, the molecular mechanism underlying peptide-mediated lysis, i.e. whether these peptides form pores or induce membrane defects, remains unclear at the atomic level. The lack of detailed oligomer structures and the involvement of complex natural cell membrane have hampered efforts to establish a direct correlation between oligomer structural transition from the aqueous to the membrane environment and their biological activity in cell membranes. Intellectual Merit: The most important goal of this project is to establish the generality of the mechanism of toxicity caused by amyloid peptides, with particular attention to two types of amyloid peptides (Aâ from Alzheimer disease vs. K3 of â2-microglobulin from hemodialysis) and two membrane interaction models (reside on the membrane vs. embed in the membrane), using a four step computational strategy coupled with different computational approaches. The specific aims of this proposal are: (i) to predict amyloid oligomers using an in house peptide packing program, (ii) to identify stable amyloid oligomers in solution, (iii) to determine toxic membrane bound oligomers and their related mechanism of membrane disruption, and (iv) to design mutants and ligands to disrupt the formation of stable toxic oligomers. The proposed synergistic four step computational strategy can be also applied to study other protein misfolding diseases such as Parkinson's and Prion diseases. Funding of this proposal will allow PI's group to extend current simulation works to capture amyloid oligomers using well controlled self-assembled monolayers and to develop polymer based inhibitors to prevent oligomer formation in experiments. In a broader context, knowing the detailed structures of amyloid oligomers and understanding their molecular behavior with lipids will (i) advance our fundamental understanding of amyloid toxicity mechanism and (ii) rationally design drugs for inhibiting amyloid formation. Broad Impact: The PI is collaborating with various experimental and theoretical groups in academia and national laboratories on this anti amyloid project. Through this research, a molecular level understanding of the relationship between structure, stability, and biological activity of misfolded protein aggregates and cell membranes can be obtained, which is vital in the development of therapeutic strategies against neurodegenerative diseases such as Alzheimer's, Parkinson's, and diabetes II, benefiting both scientific community and entire society. The project will also educate graduate, undergraduate, and precollege students, particularly those from underrepresented groups, to the concepts and simulation tools for studying protein aggregates. The discoveries and methods from this proposal will be incorporated into a new course of Molecular Modeling and Simulation of Biomolecular Systems and an existing undergraduate thermodynamics course. The knowledge derived from the proposal will be disseminated through publications, presentations, workshops, courses, internships, and other outreach activities.
淀粉样蛋白肽具有很强的膜结合能力,可通过改变膜的完整性和通透性诱导对神经元的细胞毒性。越来越多的证据表明:(i)可溶性低分子量淀粉样蛋白寡聚体是主要的毒性物质;(ii)导致细胞死亡的细胞毒性可能是通过淀粉样蛋白寡聚体与细胞膜之间的直接相互作用介导的。然而,肽介导的裂解的分子机制,即这些肽是否形成孔或诱导膜缺陷,在原子水平上仍然不清楚。缺乏详细的低聚物结构和复杂的天然细胞膜的参与,阻碍了努力建立一个直接的相关性低聚物的结构从水的膜环境和它们的生物活性在细胞膜之间的转换。智力优势:该项目最重要的目标是建立淀粉样肽引起的毒性机制的一般性,特别关注两种类型的淀粉样肽(来自阿尔茨海默病的A2与来自血液透析的A2-微球蛋白的K3)和两种膜相互作用模型(驻留在膜上与嵌入膜中),使用四步计算策略与不同的计算方法相结合。该提案的具体目标是:(i)使用内部肽包装程序预测淀粉样蛋白低聚物,(ii)鉴定溶液中稳定的淀粉样蛋白低聚物,(iii)确定毒性膜结合低聚物及其相关的膜破坏机制,以及(iv)设计突变体和配体以破坏稳定毒性低聚物的形成。所提出的协同四步计算策略也可以应用于研究其他蛋白质错误折叠疾病,如帕金森病和朊病毒疾病。该提案的资助将使PI的小组能够扩展当前的模拟工作,使用良好控制的自组装单层捕获淀粉样蛋白低聚物,并开发基于聚合物的抑制剂,以防止实验中低聚物的形成。在更广泛的背景下,了解淀粉样蛋白寡聚体的详细结构并了解其与脂质的分子行为将(i)推进我们对淀粉样蛋白毒性机制的基本理解,(ii)合理设计抑制淀粉样蛋白形成的药物。广泛影响:PI正在与学术界和国家实验室的各种实验和理论小组合作进行这项抗淀粉样蛋白项目。通过这项研究,可以在分子水平上了解错误折叠蛋白质聚集体和细胞膜的结构,稳定性和生物活性之间的关系,这对于开发针对神经退行性疾病(如阿尔茨海默氏症,帕金森氏症和糖尿病II)的治疗策略至关重要,使科学界和整个社会受益。该项目还将教育研究生,本科生和预科生,特别是那些来自代表性不足的群体,研究蛋白质聚集体的概念和模拟工具。本研究的发现和方法将被纳入一门新的生物分子系统的分子建模与模拟课程和一门现有的本科热力学课程。将通过出版物、介绍、讲习班、课程、实习和其他外联活动传播从该提案中获得的知识。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jie Zheng其他文献
Editorial: Computational data-driven design and modeling of biomolecules and biomimetics.
社论:计算数据驱动的生物分子和仿生学设计和建模。
- DOI:
10.1016/j.bpc.2022.106877 - 发表时间:
2022 - 期刊:
- 影响因子:3.8
- 作者:
Jie Zheng;Haspel Nurit;Liqun Zhang;T. Wei;Q. Shao - 通讯作者:
Q. Shao
Branched NaYF4:Yb, Er Up-Conversion Phosphors with Luminescent Properties for Anti-Counterfeiting Application
用于防伪应用的具有发光特性的支化NaYF4:Yb、Er上转换荧光粉
- DOI:
10.1166/sam.2017.3252 - 发表时间:
2017-12 - 期刊:
- 影响因子:0.9
- 作者:
Haihu Tan;Shaowen Xie;Jianxiong Xu;Na Li;Changfan Zhang;Lijian Xu;Jie Zheng - 通讯作者:
Jie Zheng
Actual Microcosmic Trace of Mantle Fluid in Deep Geological Process: Experimental Evidence with Petrography, SEM-EDS and EPMA
深层地质过程中地幔流体的实际微观痕迹:岩相学、SEM-EDS 和 EPMA 的实验证据
- DOI:
- 发表时间:
2017-09 - 期刊:
- 影响因子:0
- 作者:
Xianfan Liu;Fufeng Zhao;Chunhui Li;Xiangfeng Song;YufanYang;Jie Zheng - 通讯作者:
Jie Zheng
Influences of Flow Parameters on Pressure Drop in a Patient Specific Right Coronary Artery with Two Stenoses
流量参数对患者特定右冠状动脉两处狭窄压降的影响
- DOI:
10.1007/978-3-319-62392-4_5 - 发表时间:
2017 - 期刊:
- 影响因子:1
- 作者:
Biyue Liu;Jie Zheng;R. Bach;D. Tang - 通讯作者:
D. Tang
Single-Session Magnetic Resonance Coronary Angiography and Myocardial Perfusion Imaging Using the New Blood Pool Compound B-22956 (Gadocoletic Acid): Initial Experience in a Porcine Model of Coronary Artery Disease
使用新血池化合物 B-22956(钆胆酸)进行单次磁共振冠状动脉造影和心肌灌注成像:猪冠状动脉疾病模型的初步经验
- DOI:
- 发表时间:
2005 - 期刊:
- 影响因子:6.7
- 作者:
Jie Zheng;Debiao Li - 通讯作者:
Debiao Li
Jie Zheng的其他文献
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{{ truncateString('Jie Zheng', 18)}}的其他基金
Mechanistic Design and Understanding of Fully Polymeric Antifreezing and Tough Hydrogels
全聚合防冻剂和坚韧水凝胶的机理设计和理解
- 批准号:
2311985 - 财政年份:2023
- 资助金额:
$ 40万 - 项目类别:
Standard Grant
Rational Design and Fundamental Understanding of Multimodal Amyloid Probes
多模式淀粉样蛋白探针的合理设计和基本理解
- 批准号:
2107619 - 财政年份:2021
- 资助金额:
$ 40万 - 项目类别:
Standard Grant
MRI: Acquisition of A High-sensitivity Electrospray Ionization Mass Spectrometer for Research and Education at the University of Texas at Dallas
MRI:德克萨斯大学达拉斯分校购买高灵敏度电喷雾电离质谱仪用于研究和教育
- 批准号:
2018188 - 财政年份:2020
- 资助金额:
$ 40万 - 项目类别:
Standard Grant
Combinatorial Design and Structure-Property Relationships of Antifouling Materials
防污材料的组合设计及其结构性能关系
- 批准号:
1806138 - 财政年份:2018
- 资助金额:
$ 40万 - 项目类别:
Continuing Grant
Design of Force-Sensitive Hydrogels for Adhesives and Strain Sensors
用于粘合剂和应变传感器的力敏水凝胶的设计
- 批准号:
1825122 - 财政年份:2018
- 资助金额:
$ 40万 - 项目类别:
Standard Grant
Molecular Understanding and Design of Physically-linked Double Network Hydrogels
物理连接双网络水凝胶的分子理解和设计
- 批准号:
1607475 - 财政年份:2016
- 资助金额:
$ 40万 - 项目类别:
Continuing Grant
UNS: Design of Self-Assembling Peptides and their Conjugates as Amyloid Inhibitors
UNS:作为淀粉样蛋白抑制剂的自组装肽及其缀合物的设计
- 批准号:
1510099 - 财政年份:2015
- 资助金额:
$ 40万 - 项目类别:
Standard Grant
Molecular Design and Structural Basis of Peptide Inhibitors against Amyloid-beta Aggregation
β-淀粉样蛋白聚集肽抑制剂的分子设计和结构基础
- 批准号:
1158447 - 财政年份:2012
- 资助金额:
$ 40万 - 项目类别:
Standard Grant
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