Targeting ER Stress Pathway Using Sodium 4-Phenylbutyrate for the Treatment of POAG

使用 4-苯基丁酸钠靶向 ER 应激通路治疗 POAG

• 批准号: 9788452
• 负责人: Gulab Zode
• 金额: $ 36.5万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788452
• 关键词: Aqueous Humor; Blindness; Cell model; Cells; Chemicals; Chronic; Clinical Trials; Conduct Clinical Trials; Data; Development; Disease; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Eye; Foundations; Functional disorder; Genetic; Glaucoma; Glucocorticoids; Goals; Human; Inhibition of Matrix Metalloproteinases Pathway; Iowa; Link; MMP2 gene; MMP9 gene; Matrix Metalloproteinases; Mediator of activation protein; Modeling; Molecular Chaperones; Mus; Ocular Hypertension; Pathogenesis; Pathologic; Pathology; Pathway interactions; Perfusion; Pharmacology; Phenylbutyrates; Physiologic Intraocular Pressure; Primary Open Angle Glaucoma; Resistance; Risk Factors; Role; Signal Transduction; Sodium; Sodium phenylbutyrate; Testing; Tissues; Trabecular meshwork structure; Universities; base; chaperonin; endoplasmic reticulum stress; ex vivo perfusion; extracellular; human model; improved; inhibitor/antagonist; innovation; insight; knock-down; link protein; mouse model; mutant; myocilin; novel; prevent; protective effect; protein misfolding; transcription factor

Abstract Primary open angle glaucoma (POAG), a major cause of irreversible blindness, is often associated with elevated intraocular pressure (IOP) due to increased aqueous humor outflow resistance at the trabecular meshwork (TM). The pathological mechanisms leading to glaucomatous TM damage and IOP elevation are poorly understood. We have previously linked protein misfolding and endoplasmic reticulum (ER) stress to development of glaucomatous TM damage and IOP elevation. Importantly, we demonstrated that targeting abnormal myocilin accumulation and ER stress via small chemical chaperone, sodium 4-phenylbutyrate (PBA) rescues mouse model of myocilin glaucoma, which accounts for ~4% of general POAG. Our long-term goal is to determine whether PBA can be used for the treatment of the general POAG cases. Increased accumulation of extracellular matrix (ECM) due to reduced activity of matrix metalloproteinases (MMPs) that degrade extracellular ECM is implicated in the pathophysiology of general POAG. We have recently demonstrated that increased ECM accumulation induces chronic ER stress in the TM of POAG. Moreover, our preliminary studies suggest that PBA reduces ECM accumulation via induction and activation of MMPs. It is our central premise that increased ECM accumulation induces chronic ER stress, leading to TM dysfunction and IOP elevation in POAG and PBA reduces ECM accumulation and ER stress via induction and activation of MMPs. To test this hypothesis, we will utilize primary human TM cells and mouse models of glucocorticoid (GC) or TGFβ2-induced ocular hypertension and human perfusion cultured POAG eyes. Both GC or TGFβ2 are known to be involved in the pathophysiology of glaucomatous TM damage via increased outflow resistance and increased ECM accumulation in the TM. Based on our preliminary data that GCs activate TGFβ2 signaling, we will examine whether TGFβ2 signaling regulates GC-induced glaucoma (Aim1). Considering the major role of TGFβ2 in the pathogenesis of POAG, we will next determine whether TGFβ2 induces chronic ER stress, leading to TM dysfunction and IOP elevation via genetic knockdown of key mediators of chronic ER stress (Aim 2). In Aim 3, we will determine whether PBA improves outflow facility and prevents TGFβ2-induced ocular hypertension in mice and ex-vivo human perfusion cultured eyes. We will also determine whether PBA reduces elevated IOP via its non-chaperonin activity on induction and activation of MMPs. The proposed studies will provide pathological mechanisms of TM dysfunction and target these pathologies via PBA for the treatment of general POAG. Importantly, these studies will provide an important foundation for planned clinical trials for PBA at the University of Iowa.

摘要 原发性开角型青光眼（POAG）是不可逆性失明的主要原因，通常与 眼内压（IOP）升高，原因是小梁处的房水流出阻力增加 网状结构（TM）。导致青光眼TM损害和IOP升高的病理机制是 不太了解。我们先前已经将蛋白质错误折叠和内质网（ER）应激与 发展成青光眼性TM损伤和IOP升高。重要的是，我们证明， 通过小分子化学伴侣4-苯丁酸钠（PBA）引起的异常肌细胞素积累和ER应激 拯救肌球蛋白性青光眼小鼠模型，占一般POAG的~4%。我们的长期目标是 探讨PBA是否可用于一般性开角型青光眼的治疗。积累增加 细胞外基质（ECM）由于基质金属蛋白酶（MMPs）的活性降低， 细胞外ECM与一般POAG的病理生理学有关。我们最近已经证明， 增加的ECM积累在POAG的TM中诱导慢性ER应激。此外，我们的初步研究 提示PBA通过诱导和激活MMPs减少ECM积累。这是我们的中心前提 增加的ECM积累诱导慢性ER应激，导致TM功能障碍和IOP升高， POAG和PBA通过诱导和激活MMPs减少ECM积累和ER应激。为了验证这一 假设，我们将利用原代人TM细胞和糖皮质激素（GC）或TGFβ2诱导的小鼠模型， 高眼压和人灌注培养的POAG眼。已知GC或TGFβ2都参与了 通过增加流出阻力和增加ECM， TM中的积累。根据我们的初步数据，GC激活TGFβ2信号，我们将研究 TGFβ2信号是否调节GC诱导的青光眼（Aim 1）。考虑到TGFβ2在肿瘤发生中的主要作用， 在POAG的发病机制中，我们接下来将确定TGFβ2是否诱导慢性ER应激，导致TM 通过慢性ER应激的关键介质的遗传敲低来治疗功能障碍和IOP升高（目的2）。在目标3中， 我们将确定PBA是否能改善流出道功能并预防TGFβ2诱导的高眼压， 小鼠和离体人灌注培养的眼睛。我们还将确定PBA是否能降低升高的IOP 通过其对MMPs的诱导和激活的非伴侣蛋白活性。拟议的研究将提供 TM功能障碍的病理机制，并通过PBA靶向这些病理，用于治疗全身性 POAG。重要的是，这些研究将为计划中的PBA临床试验提供重要基础。 爱荷华州大学。