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Investigation of the Effect of Structural Modifications of Tau on Assembly State and Seeding

Tau 结构修饰对组装状态和播种影响的研究

基本信息

批准号：
10241797
负责人：
GAL BITAN
金额：
$ 13.71万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241797
关键词：
Address Administrative Supplement Affect Aging Alzheimer disease prevention Alzheimer&apos s Disease American Biochemical Biosensor Cell Line Cellular biology Complex DNA Sequence Alteration Data Development Etiology Goals Grant Health In Vitro Investigation Knowledge Methods Modification Molecular Parents Pathology Patient Care Phosphorylation Phosphorylation Site Phosphotransferases Population Post-Translational Protein Processing Process Proteins Public Health Recombinants Research Structure Structure-Activity Relationship Tauopathies Testing Toxic effect Underrepresented Minority United States National Institutes of Health Variant Work brain cell care costs effective therapy in vivo insight minority student protein phosphatase inhibitor-2 self assembly structural biology tau Proteins tau phosphorylation tau-1 therapy development

项目摘要

Abstract (from parent application) Despite significant progress in Alzheimer’s disease (AD) in general and tau pathobiology in particular, there is still no effective treatment or prevention for AD or any other tauopathy. To develop such therapy, detailed knowledge of the structural biology and structure–activity relationship of tau is needed, including the way sequence alterations and post-translational modifications affect tau self-assembly into toxic oligomers and aggregates, and how these parameters impact tau seeding and toxicity. Here, we propose a systematic, detailed study of these aspects of tau pathology taking advantage of recent developments in mass-spectrometric, biochemical, and cell biology methods. We will study the effect of primary-structure alterations and post- translational modifications on tau oligomerization and aggregation in vitro and compare recombinant and in-vivo generated tau. We will then examine how all of these factors affect tau seeding using a recently developed highly sensitive biosensor cell line. To advance therapy development, we will also test the effect of assembly modulators on tau self-assembly and seeding. A unique aspect of the project is the combination of expertise of the PI and Co-I groups, which will allow obtaining insight into the structure–activity relationship of tau on multiple levels and answering currently pending questions about the complex processes governing this crucial aspect of AD.

摘要(来自父应用程序) 尽管阿尔茨海默病(AD)总体上和tau病理生物学方面取得了重大进展，但仍有仍然没有有效的治疗或预防阿尔茨海默病或任何其他脊椎病。为了开发这种疗法，详细地需要了解tau的结构生物学和构效关系，包括序列改变和翻译后修饰影响tau自组装成有毒寡聚体和聚集体，以及这些参数如何影响tau的播种和毒性。在这里，我们提出了一个系统的、详细的利用质谱学的最新发展研究tau病理的这些方面，生物化学和细胞生物学方法。我们将研究初级结构变化和后处理的影响。体外tau寡聚和聚集的翻译修饰及其体内和重组的比较生成的牛磺酸。然后，我们将使用最近开发的一种高度敏感的生物传感器细胞系。为了推进治疗的发展，我们还将测试组装的效果基于tau自组装和播种的调制器。该项目的一个独特之处是结合了 PI和Co-I基团，这将使我们能够深入了解tau在多个并回答目前悬而未决的关于管理这一关键方面的复杂过程的问题广告。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inhibition of Staphylococcus aureus biofilm-forming functional amyloid by molecular tweezers.

通过分子镊子抑制金黄色葡萄球菌生物膜形成淀粉样蛋白。

DOI：
10.1016/j.chembiol.2021.03.013
发表时间：
2021-09-16
期刊：
CELL CHEMICAL BIOLOGY
影响因子：
8.6
作者：
Malishev, Ravit;Salinas, Nir;Gibson, James;Eden, Angela Bailey;Mieres-Perez, Joel;Ruiz-Blanco, Yasser B.;Malka, Orit;Kolusheva, Sofiya;Klaemer, Frank-Gerrit;Schrader, Thomas;Sanchez-Garcia, Elsa;Wang, Chunyu;Landau, Meytal;Bitan, Gal;Jelinek, Raz
通讯作者：
Jelinek, Raz

Lysine-selective molecular tweezers are cell penetrant and concentrate in lysosomes.

DOI：
10.1038/s42003-021-02603-2
发表时间：
2021-09-14
期刊：
Communications biology
影响因子：
5.9
作者：
Li Z;Siddique I;Hadrović I;Kirupakaran A;Li J;Zhang Y;Klärner FG;Schrader T;Bitan G
通讯作者：
Bitan G

Using FRET-Based Biosensor Cells to Study the Seeding Activity of Tau and α-Synuclein.

使用基于 FRET 的生物传感器细胞研究 Tau 和 α-突触核蛋白的接种活性。

DOI：
10.1007/978-1-0716-2597-2_10
发表时间：
2023
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Maina,KatherineN;Smet-Nocca,Caroline;Bitan,Gal
通讯作者：
Bitan,Gal

Disease-modifying therapy for proteinopathies: Can the exception become the rule?

蛋白质病的疾病修饰疗法：例外能否成为规则？

DOI：
10.1016/bs.pmbts.2019.07.010
发表时间：
2019
期刊：
Progress in molecular biology and translational science
影响因子：
0
作者：
Bitan,Gal
通讯作者：
Bitan,Gal

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice.

DOI：
10.1186/s13195-020-00743-x
发表时间：
2021-01-04
期刊：
Alzheimer's research & therapy
影响因子：
0
作者：
Di J;Siddique I;Li Z;Malki G;Hornung S;Dutta S;Hurst I;Ishaaya E;Wang A;Tu S;Boghos A;Ericsson I;Klärner FG;Schrader T;Bitan G
通讯作者：
Bitan G