Grp94-selective inhibitors to treat heredity glaucoma

Grp94选择性抑制剂治疗遗传性青光眼

基本信息

批准号：
8928624
负责人：
Brian S J Blagg
金额：
$ 41.23万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8928624
关键词：
Affect Age Alleles Alzheimer&apos s Disease Animal Model Biological Biology Blindness Cause of Death Cell Culture System Cell Death Cell Line Cell model Cells Cellular Stress Chad Clinical Collaborations Disease Drug Targeting Effectiveness Endoplasmic Reticulum Engineering Exhibits Eye Fibroblasts Genes Genetic Screening Glaucoma Goals Health Heredity Human Huntington Disease Impairment In Vitro Laboratories Lead Life Methods Modification Molecular Chaperones Mus Mutation Neurodegenerative Disorders Neurons Nonsense Mutation Optic Nerve Parents Parkinson Disease Pathway interactions Pharmaceutical Chemistry Primary Open Angle Glaucoma Property Protein Isoforms Proteins Quality Control Role Series Solubility Structure Structure-Activity Relationship System Testing Tissues Toxic effect Trabecular meshwork structure Translations Triage United States Vision Work adverse outcome base cytotoxicity empowered experience gain of function glycosylation improved inhibitor/antagonist insight mouse model mutant myocilin novel prevent prion-like small molecule therapeutic target treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Over 100,000 people in the US suffer from primary open-angle glaucoma (POAG) caused by mutations in the MYOC gene. This form of POAG results from optic nerve damage caused by the death of a protective cell network called the trabecular meshwork (TM). TM cell death occurs in these cases because mutant myocilin abnormally accumulates into toxic aggregates. This mechanism is reminiscent of neurodegenerative diseases, such as Alzheimer's, Huntington's and Parkinson's, where abnormal proteins accumulate in neurons and lead to cell death. In fact, TM cells are long-lived just like neurons. Moreover, mutations that cause earlier POAG onset also make myocilin aggregate more readily, similar to proteins associated with neurodegenerative diseases. Thus, both types of diseases can be considered "proteostasis" disorders, meaning that long-lived cells (neurons and TM) progressively lose their ability to prevent the toxic accumulation of mutant proteins with age. Thus, strategies aimed at restoring proteostasis in TM cells could be beneficial for glaucoma, just as they have proven for neurodegenerative disease. Through a series of studies, we determined that the Grp94 chaperone (an Hsp90 isoform) that resides in the endoplasmic reticulum, mistakenly preserves mutant myocilin in cells. Importantly, Grp94 only affects misfolded myocilin: Properly folded and functioning myocilin is unaffected by Grp94 manipulation. Grp94 recognizes only myocilin that is misfolded due to either mutations or impaired glycosylation: But Grp94 is unable to clear this misfolded myocilin, and instead, preserves it, causing its toxic accumulation. Thus, myocilin misfolding disrupts proteostasis by mistakenly engaging the Grp94 chaperone. We have shown that the clearance of toxic myocilin can be accelerated simply by inhibiting Grp94! Our team has developed the first isoform selective Grp94 inhibitor termed BnIm. Because the list of Grp94-dependent substrates is small, compared to other Hsp90 isoforms, the toxicity profile for this Grp94 inhibitor also appears low. Therefore, we propose to validate and improve upon this Grp94 inhibitor for the treatment of myocilin-associated POAG by establishing structure-activity relationships of Grp94 inhibitors to elucidate mechanisms of misfolded myocilin triage. We will also evaluate the biological efficacy of Grp94 inhibitors towards mutant myocilin in disease relevant systems and then work to develop Grp94 inhibitors with greater efficacy and biological activity towards misfolded myocilin. These studies will result in a new suite of Grp94 modulators and demonstrate that Grp94 is a novel clinical target to treat glaucoma caused by misfolded myocilin. In addition, mechanisms identified herein that clarify how Grp94 regulates myocilin triage could provide new insights for other proteostasis diseases.

描述（由申请人提供）：美国有超过 100,000 人患有由 MYOC 基因突变引起的原发性开角型青光眼 (POAG)。这种形式的 POAG 是由称为小梁网 (TM) 的保护性细胞网络死亡引起的视神经损伤所致。在这些情况下会发生 TM 细胞死亡，因为突变肌纤蛋白异常积累成有毒聚集体。这种机制让人想起神经退行性疾病，例如阿尔茨海默氏症、亨廷顿氏症和帕金森氏症，其中异常蛋白质在神经元中积聚并导致细胞死亡。事实上，TM细胞就像神经元一样寿命很长。此外，导致 POAG 较早发生的突变也使肌纤蛋白更容易聚集，类似于与神经退行性疾病相关的蛋白质。因此，这两种类型的疾病都可以被认为是“蛋白质稳态”疾病，这意味着长寿细胞（神经元和TM）随着年龄的增长逐渐失去防止突变蛋白毒性积累的能力。因此，旨在恢复 TM 细胞蛋白质稳态的策略可能对青光眼有益，正如它们已被证明对神经退行性疾病一样。通过一系列研究，我们确定存在于内质网中的 Grp94 分子伴侣（Hsp90 亚型）错误地将突变型肌纤蛋白保留在细胞中。重要的是，Grp94 仅影响错误折叠的肌纤蛋白：正确折叠和发挥作用的肌纤蛋白不受 Grp94 操作的影响。 Grp94 仅识别由于突变或糖基化受损而错误折叠的肌纤蛋白：但 Grp94 无法清除这种错误折叠的肌纤蛋白，而是保留它，导致其毒性积累。因此，肌纤蛋白错误折叠通过错误地与 Grp94 伴侣结合而破坏蛋白质稳态。我们已经证明，只需抑制 Grp94 即可加速有毒肌纤蛋白的清除！我们的团队开发了第一个异构体选择性 Grp94 抑制剂，称为 BnIm。由于 Grp94 依赖性底物列表较少，与其他 Hsp90 同工型相比，该 Grp94 抑制剂的毒性特征也较低。因此，我们建议通过建立 Grp94 抑制剂的结构-活性关系来验证和改进这种 Grp94 抑制剂治疗肌纤蛋白相关 POAG 的效果，以阐明错误折叠肌纤蛋白分类的机制。我们还将评估Grp94抑制剂在疾病相关系统中对突变肌纤蛋白的生物学功效，然后致力于开发对错误折叠肌纤蛋白具有更高功效和生物活性的Grp94抑制剂。这些研究将产生一套新的 Grp94 调节剂，并证明 Grp94 是治疗由错误折叠肌纤蛋白引起的青光眼的新临床靶点。此外，本文确定的阐明 Grp94 如何调节肌纤蛋白分类的机制可以为其他蛋白质稳态疾病提供新的见解。