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.

项目概要/摘要脊髓延髓性肌萎缩症 (SBMA) 是一种无法治愈的神经退行性疾病，其特征是突变雄激素受体 (polyQ-AR) 蛋白的毒性积累所致。分子伴侣蛋白 DnaJB6 专门用于防止细胞中的 polyQ-AR 聚集，并通过预防来抑制疾病表型 polyQ-AR 聚集并将另一种伴侣蛋白 Hsp70 募集到 polyQ-AR。而 DnaJB6 代表 SBMA 化疗药物的开发令人兴奋的目标，其动态的蛋白质-蛋白质相互作用和复杂的结构对发现和设计 DnaJB6 化学配体的努力提出了重大挑战。 DnaJB6 与其自身结合形成复合物，似乎在较大和较小的之间进行交换随着时间的推移寡聚状态。我假设与 polyQ-AR 或 Hsp70 的结合会导致 DnaJB6 复合物的稳定性，并且可以利用 DnaJB6 动力学的这些变化来发现化学探针。然后，DnaJB6 化学探针可用于探测 SBMA 中的病理聚集。到检验这个假设，我将表征 DnaJB6 复合物的稳定性并发现调节 DnaJB6 的化学物质本次奖励K99阶段活动。在R00阶段，我将使用这些分子来探测细胞中的SBMA并动物模型。这项工作意义重大，因为我的研究成果不仅具有适用性用于研究 SBMA，还用于 DnaJB6 可以抑制蛋白质的其他神经退行性疾病聚集（即亨廷顿病、脊髓小脑性共济失调和帕金森病）和伴侣更广泛的生物学。我提出的研究具有创新性，因为它们将产生第一个针对 DnaJB6 的化学物质探针和新策略来了解 SBMA 的分子基础。