Molecular Mechanisms of SOD1-linked ALS (P01)

SOD1 相关 ALS 的分子机制 (P01)

基本信息

批准号：
8644318
负责人：
JOAN Selverstone VALENTINE
金额：
$ 95.03万
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：
2005
资助国家：
美国
起止时间：
2005-08-11 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8644318
关键词：
Address Amyloid Fibrils Amyotrophic Lateral Sclerosis Animal Disease Models Animal Model Award Biochemical Biological Assay Biological Models Cell Culture Techniques Cessation of life Collaborations Data Disease Disease Progression Disease model Disulfides Etiology Familial Amyotrophic Lateral Sclerosis Gene Mutation Goals Homeostasis Human In Vitro Investigation Lead Link Metals Methods Modeling Molecular Molecular Weight Motor Neurons Mus Mutation Neurodegenerative Disorders Neuroglia Pathogenesis Patients Preparation Principal Investigator Process Property Proteins Research Personnel Role Source Spinal Cord Stem cells Structure Study models Symptoms Testing Tissues Toxic effect Vertebral column Work animal tissue biophysical techniques copper zinc superoxide dismutase design efficacy testing human tissue in vivo inhibitor/antagonist instrumentation mutant programs public health relevance

项目摘要

DESCRIPTION (provided by applicant): This Program Project brings together five researchers with very different expertise and experimental capabilities to work together on elucidating the underlying mechanisms of S0D1-linked familial amyotrophic lateral sclerosis (fALS) pathogenesis. It is well established that S0D1 multimers and larger aggregates are associated with disease but the toxic species and in vivo mechanism remain unknown. The overall goals of this proposal are to gain an extensive understanding of the role of aggregation in disease, to characterize further the biochemical properties associated with mutant S0D1 and its aggregation, to uncover clues about the initiation and progression of disease, to exploit this understanding to develop targeted blockers of multimerization. The PPG collaboration will encompass five primary investigators with four projects and a technical Core. Projects 1 (Dr. Joan Valentine) and 4 (Dr. David Eisenberg) will take an in vitro structural and biophysical approach to studying the mechanism of S0D1 multimerization and the structures of the multimers, with the goals of understanding the mechanism(s) of multimerization and designing inhibitors of aggregation. Project 2 (Dr. Martina Wiedau-Pazos) will use stem cell-derived motor neurons and glia and project 3 (Dr. David Borchelt) will use a mouse,and cell culture models to probe the toxicity of multimers and to characterize the changes in mutant S0D1 that lead toward disease. A particular emphasis on the latter project will be toward in vivo metal loading as it pertains to S0D1 stability, and metal homeostasis as it pertains toward cellular toxicity. Core A (Dr. Julian Whitelegge) will serve as the backbone of these investigations by providing and maintaining the necessary instrumentation and data delivery. Disease models from projects 2 and 3 will be used to test the efficacy of inhibitors from projects 1 and 4. Finally, ALS tissue will be used as a source to validate the findings and test new hypotheses.

描述（由申请人提供）：该计划项目汇集了五名具有截然不同的专业知识和实验能力的研究人员，以阐明S0D1连接的家族性肌萎缩性侧面硬化症（FALS）发病机理的基础机制。众所周知，S0D1多聚体和较大的聚集体与疾病相关，但是有毒物种和体内机制仍然未知。该提案的总体目标是广泛了解聚集在疾病中的作用，以进一步表征与突变体S0D1及其聚集相关的生化特性，以发现有关疾病起始和进展的线索，以利用这种理解以发展目标障碍物的靶向障碍者。 PPG合作将涵盖五名主要研究人员，其中有四个项目和一个技术核心。项目1（Joan Valentine博士）和4（David Eisenberg博士）将采用一种体外的结构和生物物理方法来研究S0D1多聚化的机制和多聚体的结构，并了解了共同聚集的多物质化和设计抑制剂的机制的目标。 Project 2（Martina Wiedau-Pazos博士）将使用干细胞衍生的运动神经元和GLIA和Project 3（David Borchelt博士）（David Borchelt博士）将使用小鼠，并使用细胞培养模型来探测多聚体的毒性，并表征突变体S0D1的变化，导致疾病。对后一个项目的特别强调将是与S0D1稳定性有关的体内金属载荷，而金属稳态与细胞毒性有关。核心A（Julian Whitelegge博士）将通过提供和维护必要的仪器和数据传递来充当这些调查的骨干。项目2和3的疾病模型将用于测试项目1和4的抑制剂的功效。最后，ALS组织将被用作验证发现并检验新假设的来源。

项目成果

期刊论文数量（31）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An analysis of interactions between fluorescently-tagged mutant and wild-type SOD1 in intracellular inclusions.

细胞内包涵体中荧光标记突变体和野生型 SOD1 之间相互作用的分析。

DOI：
10.1371/journal.pone.0083981
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Qualls,DavidA;Crosby,Keith;Brown,Hilda;Borchelt,DavidR
通讯作者：
Borchelt,DavidR

Unbiased screen reveals ubiquilin-1 and -2 highly associated with huntingtin inclusions.

DOI：
10.1016/j.brainres.2013.06.006
发表时间：
2013-08-02
期刊：
Brain research
影响因子：
2.9
作者：
Rutherford NJ;Lewis J;Clippinger AK;Thomas MA;Adamson J;Cruz PE;Cannon A;Xu G;Golde TE;Shaw G;Borchelt DR;Giasson BI
通讯作者：
Giasson BI

Substantially elevating the levels of αB-crystallin in spinal motor neurons of mutant SOD1 mice does not significantly delay paralysis or attenuate mutant protein aggregation.

显着提高突变型 SOD1 小鼠脊髓运动神经元中 αB-晶状体蛋白的水平不会显着延迟麻痹或减弱突变蛋白聚集。

DOI：
10.1111/jnc.13022
发表时间：
2015
期刊：
Journal of neurochemistry
影响因子：
4.7
作者：
Xu,Guilian;Fromholt,Susan;Ayers,JacobI;Brown,Hilda;Siemienski,Zoe;Crosby,KeithW;Mayer,ChristopherA;Janus,Christopher;Borchelt,DavidR
通讯作者：
Borchelt,DavidR

Role of disulfide cross-linking of mutant SOD1 in the formation of inclusion-body-like structures.

突变体 SOD1 的二硫键交联在包涵体样结构形成中的作用。

DOI：
10.1371/journal.pone.0047838
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Roberts,BrittanyLT;Patel,Kinaree;Brown,HildaH;Borchelt,DavidR
通讯作者：
Borchelt,DavidR

Features of wild-type human SOD1 limit interactions with misfolded aggregates of mouse G86R Sod1.

野生型人类 SOD1 的特征限制了与小鼠 G86R Sod1 错误折叠聚集体的相互作用。

DOI：
10.1186/1750-1326-8-46
发表时间：
2013
期刊：
Molecular neurodegeneration
影响因子：
15.1
作者：
Qualls,DavidA;Prudencio,Mercedes;Roberts,BrittanyLT;Crosby,Keith;Brown,Hilda;Borchelt,DavidR
通讯作者：
Borchelt,DavidR