权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Probing the roles of membrane and cholesterol on Aβ biogenesis and prion protein interactions

探讨膜和胆固醇对 Aβ 生物合成和朊病毒蛋白相互作用的作用

基本信息

批准号：
10379243
负责人：
JOHN E. STRAUB
金额：
$ 37.94万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379243
关键词：
Address Affect Alzheimer&apos s Disease Amyloid Proteins Amyloid beta-Protein Amyloid beta-Protein Precursor Area Binding Biogenesis Biophysics Brain Cause of Death Cell Surface Receptors Characteristics Cholesterol Collaborations Complex Computer Models Computer Simulation Computing Methodologies Development Disease Early Onset Alzheimer Disease Elderly Environment Enzymes Future Goals Growth Heterogeneity In Vitro Knowledge Link Lipids Mediating Membrane Membrane Lipids Membrane Microdomains Membrane Proteins Methods Molecular Mutation Neurodegenerative Disorders Outcome Pathogenicity Pathway interactions Play Population PrP Preventive Probability Process Production Proteins Proteolytic Processing Research Research Proposals Role Route Senile dementia Structure Symptoms System Therapeutic Toxic effect Transmembrane Domain United States abeta accumulation abeta oligomer amyloid precursor protein processing cofactor computer studies conformational conversion cytotoxicity experimental study familial Alzheimer disease fundamental research insight monomer neuron loss novel protein aggregation protein function receptor receptor binding secretase simulation theories

项目摘要

Project Summary Aggregation of proteins of known sequence is linked to a variety of neurodegenerative disorders. Familial mutations in the Amyloid Precursor Protein (APP), from which the amyloid β (Aβ) protein is derived, have been linked with the early onset of Alzheimer's disease (AD). After fifteen years of fundamental research using computer simulations guided by experiments to identify the factors that determine in vitro aggregation of Aβ, the stage is now set to address questions of utmost relevance to AD. They arise in the context of how heterogeneous membrane environments, cholesterol, and downstream interactions with cofactors affect the cleavage of APP, the production of Aβ, and subsequent interactions of Aβ oligomers and receptors mediating their toxic effects. We are uniquely poised to use computational models to answer these questions and drive advances in critical areas of AD research. In this computational and theoretical research proposal, augmented by synergistic experimental research collaborations, we address fundamental biophysical questions with substantial practical implications articulated in three specific aims. (1) Developing a quantitative understanding of how membrane lipid composition and structural heterogeneity impacts the partitioning of APP and secretases critical to the processing of APP in the genesis Aβ. (2) Elucidating the crucial role cholesterol plays in determining the extent of amyloidogenic cleavage in the differential processing of APP. (3) Characterizing at the molecular-level the conformational transitions and interactions involved in the binding of Aβ monomer and oligomers to cellular prion protein (PrPC), implicated in a plausible mechanism of Aβ cytotoxicity. The proposed coordinated studies will lead to a fundamental molecular-level understanding of the network of interactions that are essential to the biogenesis of Aβ protein and its role as a pathogenic agent in AD. Through the development of novel computational models and identification of new concepts, the expected outcomes could change the landscape for the use of simulations and theory not only in the AD field but also in the general study of membrane- protein interactions.!

项目概要已知序列蛋白质的聚集与多种神经退行性疾病有关失调。淀粉样前体蛋白 (APP) 的家族突变，β 淀粉样蛋白源自该蛋白 (Aβ) 蛋白衍生而来，与阿尔茨海默病 (AD) 的早期发病有关。后十五年的基础研究，使用以实验为指导的计算机模拟确定了决定 Aβ 体外聚集的因素，现在的阶段是解决与 AD 最相关的问题。它们是在异构的背景下出现的膜环境、胆固醇和下游与辅因子的相互作用影响 APP 的裂解、Aβ 的产生以及随后 Aβ 寡聚物和受体介导其毒性作用。我们独特地准备使用计算模型来回答这些问题并推动 AD 研究关键领域的进步。在这个计算和理论研究提案中，通过协同实验进行了增强研究合作，我们通过大量的研究来解决基本的生物物理问题三个具体目标中阐述的实际影响。 (1) 制定量化的了解膜脂组成和结构异质性如何影响 APP 和分泌酶的分配对于起源 Aβ 中 APP 的加工至关重要。 (2) 阐明胆固醇在确定淀粉样蛋白生成程度中的关键作用 APP差异加工中的裂解。 (3) 在分子水平上表征 Aβ单体和结合所涉及的构象转变和相互作用细胞朊病毒蛋白 (PrPC) 的寡聚物，涉及 Aβ 细胞毒性的合理机制。拟议的协调研究将导致对分子水平的基本理解对 Aβ 蛋白的生物合成及其作为蛋白质的作用至关重要的相互作用网络 AD 中的病原体。通过开发新颖的计算模型和识别新概念，预期结果可能会改变使用格局模拟和理论不仅在 AD 领域，而且在膜的一般研究中蛋白质相互作用.!

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure of APP-C991-99 and implications for role of extra-membrane domains in function and oligomerization.

APP-C991-99 的结构以及膜外结构域在功能和寡聚化中的作用的影响。

DOI：
10.1016/j.bbamem.2018.04.002
发表时间：
2018
期刊：
Biochimica et biophysica acta. Biomembranes
影响因子：
0
作者：
Pantelopulos,GeorgeA;Straub,JohnE;Thirumalai,D;Sugita,Yuji
通讯作者：
Sugita,Yuji

Molecular Insights into Human Hereditary Apolipoprotein A-I Amyloidosis Caused by the Glu34Lys Mutation.

Glu34Lys 突变引起的人类遗传性载脂蛋白 A-I 淀粉样变性的分子见解。

DOI：
10.1021/acs.biochem.8b00817
发表时间：
2018
期刊：
Biochemistry
影响因子：
2.9
作者：
Morgado,Isabel;Panahi,Afra;Burwash,AndrewG;Das,Madhurima;Straub,JohnE;Gursky,Olga
通讯作者：
Gursky,Olga

Extension of a protein docking algorithm to membranes and applications to amyloid precursor protein dimerization.