The AR N/C interaction in SBMA - Mechanistic role and therapeutic potential

SBMA 中的 AR N/C 相互作用 - 机制作用和治疗潜力

• 批准号: 10112974
• 负责人: DIANE E MERRY
• 金额: $ 46.62万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112974
• 关键词: AF2; Ablation; Adult; Agonist; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Androgen Receptor; Androgens; Animal Model; Binding; Cell Nucleus; Cell model; Cells; Characteristics; Clinical Trials; DNA Binding; Development; Dimerization; Disease; Disease Progression; Disease model; Evaluation; Event; Failure; Family; Genetic; Genetic Transcription; Goals; Hormonal; Hormones; Huntington Disease; In Vitro; Inherited; Lead; Ligand Binding Domain; Ligands; Link; Lysine; Mediating; Metabolism; Modeling; Molecular; Molecular Conformation; Motor Neurons; Mus; Muscle function; Mutation; Nature; Neurodegenerative Disorders; Neuromuscular Diseases; Neuronal Dysfunction; Nuclear; Observational Study; Parkinson Disease; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Process; Property; Proteins; Proteomics; Receptor Aggregation; Role; Seeds; Serine; Spinocerebellar Ataxias; Structure; Tertiary Protein Structure; Testing; Testosterone; Therapeutic; Toxic effect; Transgenic Mice; Work; androgen deprivation therapy; androgenic; base; efficacy testing; in vivo; in vivo Model; insight; mouse model; mutant; neuron loss; neuroprotection; novel therapeutics; polyglutamine; prevent; protein misfolding; public health relevance; receptor; response; selective androgen receptor modulator; spinal and bulbar muscular atrophy; therapeutic target

Project Summary: Many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and the polyglutamine diseases, result from protein misfolding and accumulation due to a variety of genetic and/or environmental causes. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, inherited neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR); it is related to other neurodegenerative diseases caused by polyglutamine expansion, including Huntington's disease and several spinocerebellar ataxias. Although the precise pathway leading to neuronal dysfunction and death is unknown, the evaluation of transgenic mouse and cell models of these diseases has yielded mechanistic insights to disease pathogenesis. SBMA stands apart from other polyglutamine diseases in that its onset and progression are dependent on AR androgenic ligands. Our cell and mouse models of SBMA reproduce the androgen- and polyglutamine-dependent nuclear AR aggregation seen in patients, as well as its consequent toxicity, making these models highly useful for the analysis of the mechanistic basis for upstream events involved in AR toxicity. Our long-term objectives are to use these models to develop a mechanistic understanding of steps in SBMA pathogenesis that occur in response to hormone binding and to develop therapeutic approaches based on that understanding. Our previous studies revealed that a specific conformational state of the AR that occurs upon hormone binding, the N/C interaction, is required for its aggregation and toxicity; inhibition of the N/C interaction is protective in both in vitro and in vivo models. Moreover, we found that Ser-16 phosphorylation is required for this protection. We propose in this application to further understand the mechanism underlying the role of both the AR N/C interaction and Ser-16 phosphorylation in disease. In addition, we propose to screen selective AR modulators (SARMs) that prevent the AR N/C interaction for their effects on SBMA pathogenesis, both in vitro and in vivo. We anticipate that results from these studies will lead us to a new understanding of the molecular pathogenesis of SBMA and enhance our development of new therapies for SBMA.

项目摘要： 许多神经退行性疾病，包括阿尔茨海默病，帕金森病和 多聚谷氨酰胺疾病是由多种遗传因素引起的蛋白质错误折叠和积累引起的， 和/或环境原因。脊髓延髓肌萎缩症（SBMA）是一种成人发病，遗传性， 由雄激素受体（AR）内的多聚谷氨酰胺扩增引起的神经肌肉疾病; 它与多聚谷氨酰胺扩增引起的其他神经退行性疾病有关，包括 亨廷顿氏病和几种脊髓小脑共济失调。虽然通往 神经元功能障碍和死亡是未知的，评价转基因小鼠和细胞模型， 这些疾病已经产生了对疾病发病机理的机械见解。SBMA除了 其他多聚谷氨酰胺疾病，因为其发病和进展依赖于AR雄激素 配体。我们的SBMA细胞和小鼠模型再现了雄激素和多聚谷氨酰胺依赖的 在患者中观察到的核AR聚集，以及随之而来的毒性，使得这些模型 对于AR毒性中涉及的上游事件的机制基础的分析非常有用。我们 长期目标是使用这些模型来发展对步骤的机械理解 在SBMA发病机制中，发生在对激素结合的反应中， 基于这种理解的方法。我们之前的研究表明， 在激素结合时发生的AR的构象状态，N/C相互作用，是 其聚集和毒性;抑制N/C相互作用在体外和体内均具有保护作用 模型此外，我们发现Ser-16磷酸化是这种保护所必需的。我们提出 在本申请中，为了进一步理解AR N/C 相互作用和Ser-16磷酸化。此外，我们建议筛选选择性AR 调节剂（SARM），其阻止AR N/C相互作用以影响SBMA发病机制， 无论是在体外还是在体内。我们预计，这些研究的结果将引导我们找到一种新的 了解SBMA的分子发病机制，促进我们开发新的 治疗SBMA。