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

基本信息

批准号：
10341213
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10341213
关键词：
AF2 Ablation Adult Agonist Alzheimer&apos 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 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

项目摘要

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.

项目概要：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导致的蛋白质错误折叠和积累引起的和/或环境原因。脊髓和延髓肌萎缩症 (SBMA) 是一种成人发病的遗传性由雄激素受体 (AR) 内的聚谷氨酰胺扩张引起的神经肌肉疾病；它与多聚谷氨酰胺扩张引起的其他神经退行性疾病有关，包括亨廷顿舞蹈症和几种脊髓小脑性共济失调。虽然通往的精确路径神经元功能障碍和死亡尚不清楚，转基因小鼠和细胞模型的评估这些疾病为疾病发病机制提供了机制见解。 SBMA 与众不同其他多聚谷氨酰胺疾病，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谷氨酰胺依赖性在患者体内观察到的核 AR 聚集及其随之而来的毒性，使这些模型成为可能对于分析 AR 毒性相关上游事件的机制基础非常有用。我们的长期目标是使用这些模型来形成对步骤的机械理解 SBMA 发病机制是对激素结合的反应，并开发治疗方法基于这种理解的方法。我们之前的研究表明，一个特定的激素结合时发生的 AR 构象状态，即 N/C 相互作用，是其聚集性和毒性；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。我们建议在此应用中，可以进一步了解 AR N/C 的作用背后的机制疾病中的相互作用和 Ser-16 磷酸化。此外，我们建议筛选选择性AR 调节剂（SARM）可防止 AR N/C 相互作用对 SBMA 发病机制的影响，体外和体内。我们预计这些研究的结果将引导我们得出新的结论了解 SBMA 的分子发病机制并促进我们新药的开发 SBMA 的治疗方法。