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（来自父申请）尽管阿尔茨海默氏病（AD），特别是 tau 病理学研究取得了重大进展，但仍然没有有效的治疗或预防 AD 或任何其他 tau 蛋白病的方法，详细介绍。需要了解 tau 的结构生物学和结构-活性关系，包括其方式序列改变和翻译后修饰会影响 tau 自组装成有毒寡聚体聚集体，以及这些参数如何影响 tau 播种和毒性。在这里，我们提出了一个系统的、详细的方案。利用质谱的最新发展来研究 tau 病理学的这些方面，我们将研究一级结构改变和后处理的影响。体外 tau 寡聚和聚集的翻译修饰并比较重组和体内然后，我们将使用最近开发的方法来研究所有这些因素如何影响 tau 播种。为了推进疗法的开发，我们还将测试组装的效果。该项目的一个独特之处是结合了 tau 自组装和播种的调节剂。 PI 和 Co-I 组，这将允许深入了解 tau 在多个水平并回答目前悬而未决的有关管理这一关键方面的复杂流程的问题广告。

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.

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

The recent failure of the PROMESA clinical trial for multiple system atrophy raises the question-are polyphenols a viable therapeutic option against proteinopathies?

DOI：
10.21037/atm.2020.01.117
发表时间：
2020-06-01
期刊：
ANNALS OF TRANSLATIONAL MEDICINE
影响因子：
0
作者：
Bitan, Gal
通讯作者：
Bitan, Gal

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

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

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？