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.

抽象的 原发性开头青光眼（POAG）是不可逆失明的主要原因，通常与 由于在小梁处的水性幽默出口电阻增加，眼内压（IOP）升高 网格工作（TM）。导致青光眼TM损伤和IOP升高的病理机制是 理解不佳。我们以前已将蛋白质折叠和内质网（ER）应力联系在一起 青光眼TM损伤和IOP升高的发展。重要的是，我们证明了目标 肌动蛋白异常的积累和ER应激通过小型化学伴侣，4-苯基丁酸钠（PBA） 营救肌动蛋白青光眼的小鼠模型，该模型约占一般POAG的4％。我们的长期目标是 确定PBA是否可以用于治疗一般POAG病例。积累增加 由于降解降解的基质金属蛋白酶（MMP）的活性降低，细胞外基质（ECM） 一般POAG的病理生理学暗示了细胞外ECM。我们最近证明了 ECM积累的增加会诱导POAG TM中的慢性ER应激。而且，我们的初步研究 表明PBA通过诱导和激活MMPS降低ECM的积累。这是我们的中央前提 ECM积累的增加会引起慢性ER应力，导致TM功能障碍和IOP升高 POAG和PBA通过诱导和激活MMP来减少ECM的积累和ER应力。测试这个 假设，我们将利用糖皮质激素（GC）或TGFβ2诱导的原代人TM细胞和小鼠模型 眼高血压和人类灌注培养的Poag Eyes。已知GC或TGFβ2参与 通过增加的出口电阻和ECM增加的青光眼TM损伤的病理生理 在TM中积累。基于我们的初步数据，GCS激活TGFβ2信号，我们将检查 TGFβ2信号传导是否调节GC诱导的青光眼（AIM1）。考虑到TGFβ2在 POAG的发病机理，我们接下来确定TGFβ2是否诱导慢性ER应激，导致TM 功能障碍和IOP升高通过遗传敲低慢性ER应力的介体的遗传敲低（AIM 2）。在AIM 3中， 我们将确定PBA是否改善了输出设施并防止TGFβ2诱导的眼高血压 小鼠和前体灌注培养的眼睛。我们还将确定PBA是否降低了IOP的升高 通过其非链球菌素活性对MMP的诱导和激活。拟议的研究将提供 TM功能障碍的病理机制，并通过PBA靶向这些病理学来治疗一般 Poag。重要的是，这些研究将为PBA计划的临床试验提供重要的基础 爱荷华大学。