Developing Tools to Probe DnaJB6 Dynamics in Spinobulbular Muscular Atrophy

开发工具来探测脊髓球性肌萎缩症中的 DnaJB6 动力学

基本信息

批准号：
10515844
负责人：
Oleta Tanitrea Johnson
金额：
$ 11.88万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10515844
关键词：
ATP phosphohydrolase Androgen Receptor Animal Model Award Binding Biochemical Biological Assay Biology Biophysics C10 Cell model Cells Chemicals Complex Disease Progression Drug Targeting Electron Microscopy Future Genetic Diseases Goals Homo Huntington Disease In Vitro Libraries Ligands Maps Methods Modeling Molecular Molecular Chaperones Molecular Sieve Chromatography Muscular Atrophy Mutate Neurodegenerative Disorders Parkinson Disease Pathologic Peptides Phase Photometry Proteins Role Scanning Site Solvents Spinobulbar Muscular Atrophy Spinocerebellar Ataxias Structure Structure-Activity Relationship Surface Plasmon Resonance System Techniques Testing Time Toxic effect Training Work base design disease phenotype improved in vitro activity innovation light scattering molecular dynamics mouse model mutant neuromuscular novel novel strategies polyglutamine prevent protein aggregation protein protein interaction proteostasis receptor recruit small molecule tool

项目摘要

PROJECT SUMMARY/ABSTRACT Spinobulbar Muscular Atrophy (SBMA) is an incurable neurodegenerative disorder that is characterized by the toxic accumulation of mutated androgen receptor (polyQ-AR) proteins. The molecular chaperone protein DnaJB6 is specialized to prevent polyQ-AR aggregation in cells and suppress disease phenotypes by preventing polyQ-AR aggregation and recruiting another chaperone protein, Hsp70 to polyQ-AR. While DnaJB6 represents an exciting target for developing SBMA chemotherapeutics, its dynamic protein-protein interactions and complex structure present significant challenges for efforts to discover and design DnaJB6 chemical ligands. DnaJB6 associates with itself to form complexes that appear to exchange between larger and smaller oligomeric states over time. I hypothesize that binding to either polyQ-AR or Hsp70 causes changes in the stability of DnaJB6 complexes, and that these changes in DnaJB6 dynamics can be exploited to discover chemical probes. DnaJB6 chemical probes could then be used to probe pathological aggregation in SBMA. To test this hypothesis, I will characterize DnaJB6 complex stability and discover chemical matter that tunes DnaJB6 activity in the K99 phase of this award. In the R00 phase, I will use these molecules to probe SBMA in cell and animal models. This work is significant because the tools resulting from my studies will not only have applicability for studying SBMA, but also for other neurodegenerative disease where DnaJB6 can suppress protein aggregation (i.e. Huntington's Disease, Spinocerebellar Ataxias, and Parkinson's Disease) and chaperone biology more broadly. My proposed studies are innovative, as they will yield the first DnaJB6-targeted chemical probes and a novel strategy to understand the molecular underpinnings of SBMA.

项目摘要/摘要脊柱肌萎缩症（SBMA）是一种无法治愈的神经退行性疾病，其特征是突变的雄激素受体（PolyQ-AR）蛋白的有毒积累。分子伴侣蛋白 DNAJB6专门用于防止细胞中的PolyQ-AR聚集，并通过防止抑制疾病表型 PolyQ-AR聚集并募集另一种伴侣蛋白HSP70至PolyQ-AR。而DNAJB6代表开发SBMA化学疗法，动态蛋白质蛋白质相互作用和复杂的一个令人兴奋的靶标结构为发现和设计DNAJB6化学配体的努力提出了重大挑战。 DNAJB6与自己相关联，形成似乎在较大和较小之间交换的复合物寡聚状态随着时间的流逝。我假设与PolyQ-AR或HSP70结合会导致变化 DNAJB6复合物的稳定性，并且可以利用DNAJB6动力学中的这些变化以发现化学探针。然后，DNAJB6化学探针可用于探测SBMA中的病理聚集。到检验该假设，我将表征DNAJB6复合稳定性并发现调谐DNAJB6的化学物质该奖项的K99阶段的活动。在R00阶段，我将使用这些分子在细胞中探测SBMA和动物模型。这项工作很重要，因为我的研究产生的工具不仅具有适用性用于研究SBMA，还用于其他神经退行性疾病，DNAJB6可以抑制蛋白聚集（即亨廷顿氏病，脊椎小脑共济失调和帕金森氏病）和伴侣生物学更广泛。我提出的研究是创新的，因为它们将产生第一个靶向DNAJB6的化学物质探针和一种了解SBMA分子基础的新型策略。