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）：美国超过100,000人患有由MYOC基因突变引起的主要开放角度青光眼（POAG）。这种形式的POAG是由于视神经损伤是由称为小梁网（TM）的保护性细胞网络引起的。 TM细胞死亡发生在这些情况下，因为突变肌动蛋白异常积聚成有毒骨料。这种机制让人联想到神经退行性疾病，例如阿尔茨海默氏症，亨廷顿和帕金森氏症，那里异常蛋白质在神经元中积累并导致细胞死亡。实际上，TM细胞就像神经元一样长。此外，引起早期POAG发作的突变也使肌动蛋白骨料更容易，类似于与神经退行性疾病相关的蛋白质。因此，两种类型的疾病都可以视为“蛋白质抑制”疾病，这意味着长寿命细胞（神经元和TM）逐渐失去了防止随着年龄的增长的突变蛋白的毒性积累的能力。因此，旨在恢复TM细胞中蛋白质的策略可能对青光眼有益，就像它们已证明是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伴侣（HSP90同工型），错误地保留了细胞中突变的肌动蛋白。重要的是，GRP94仅影响肌动蛋白错误折叠：正确折叠和功能性肌动蛋白不受GRP94操纵的影响。 GRP94仅识别由于突变或糖基化受损而被错误折叠的肌动蛋白：但是GRP94无法清除这种错误折叠的肌动蛋白，而是保留它，从而导致其有毒积累。因此，肌动蛋白错误折叠通过错误地与GRP94伴侣伴侣互动来破坏蛋白质的。我们已经表明，仅通过抑制GRP94来加速有毒肌动蛋白的清除！我们的团队开发了第一个称为BNIM的同工型选择性GRP94抑制剂。由于与其他HSP90同工型相比，GRP94依赖性底物的列表很小，因此该GRP94抑制剂的毒性特征也显得很低。因此，我们建议通过建立GRP94抑制剂的结构 - 活性关系来阐明肌动蛋白分类错误的机制，以验证和改进该GRP94抑制剂治疗与肌动蛋白相关的POAG的治疗。我们还将评估GRP94抑制剂对疾病相关系统中突变体肌动蛋白的生物学疗效，然后努力开发具有更大功效和生物学活性对肌动蛋白折叠率折叠率更高的GRP94抑制剂。这些研究将导致新的GRP94调节剂套件，并证明GRP94是治疗由肌动蛋白折叠率折叠引起的青光眼的新型临床靶标。此外，本文确定的机制阐明了GRP94如何调节肌动蛋白分类可以为其他蛋白质疾病提供新的见解。