Tissue plasminogen activator for the treatment of glaucoma

用于治疗青光眼的组织纤溶酶原激活剂

• 批准号: 10642977
• 负责人: John Danias
• 金额: --
• 依托单位: VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642977
• 关键词: Adolescent; Adverse effects; Affect; Alteplase; Animals; Aqueous Humor; Axon; Binding; Blindness; Cell Count; Cellular Morphology; Chronic; Development; Disease; Electroretinography; Endothelial Cells; Extracellular Signal Regulated Kinases; Eye; Facility Regulation; Gelatinase B; Gene Mutation; Glaucoma; Goals; Health; Histology; Human; LDL-Receptor Related Protein 1; Life; Link; Lipoprotein Receptor; MAPK3 gene; Measures; Mediating; Minority; Molecular; Monitor; Mutation; Nerve Degeneration; Open-Angle Glaucoma; Optic Nerve; Pathology; Pathway interactions; Pattern; Personal Satisfaction; Physiologic Intraocular Pressure; Play; Prevention; Proteins; Retina; Retinal Ganglion Cells; Risk; Risk Factors; Role; Safety; Serine Protease; Signal Transduction; Site; Steroids; Supplementation; Testing; Therapeutic Uses; Time; Tissues; Toxic effect; Transgenic Animals; Transgenic Mice; Up-Regulation; Variant; Veterans; Vision; Visual Acuity; efficacy evaluation; efficacy testing; functional loss; improved; in vivo; modifiable risk; mutant; myocilin; novel therapeutics; optic nerve disorder; overexpression; pharmacologic; preservation; prevent; receptor; response; retinal toxicity

Open angle glaucoma (OAG) is a group of progressive optic neuropathies that can lead to blindness. It is a serious health issue among minorities and veterans who are disproportionately affected by the disease. OAG pathology involves increased IOP which is the result of reduced outflow facility of the aqueous humor. High IOP increases the risk for both development and progression of glaucomatous neurodegeneration and functional loss. Although current therapies of OAG are directed at lowering IOP, few if any target the site of pathology in the outflow tissues or increase outflow facility. Tissue plasminogen activator (tPA) is a serine protease that has an important role in outflow facility regulation. We have shown that tPA is reduced in steroid-induced IOP elevation and that outflow facility is reduced in tPA (PLAT)-null animals. Furthermore, exogenous supplementation of tPA reverses outflow facility reduction and IOP elevation in both steroid-induced glaucoma as well as in tPA null animals. We have also surprisingly shown that tPA and enzymatically inactive tPA (EI-tPA) can improve outflow facility in human mutant myocilin transgenic animals. We propose here to determine the efficacy and safety of using tPA and EI-tPA as a long-term treatment for OAG, and elucidate the molecular mechanisms through which tPA causes its effect on outflow facility. Our hypothesis is that overexpression of EI-tPA in the outflow tissues is safe and effective in the treatment of OAG and results in preservation of vision. Furthermore, we hypothesize that EI-tPA causes matrix metalloproteinase 9 (MMP9) upregulation through the Low-density lipoprotein Receptor-related Protein (LRP) receptors and Extracellular signal-Regulated Kinase (ERK) signaling. To test this hypothesis, we propose the following specific aims: Specific Aim 1: Determine whether chronic treatment with tPA or EI-tPA can be used to treat glaucoma and prevent functional damage from the disease. Specific Aim 2: Determine whether chronic treatment with tPA or EI-tPA causes retinal or other eye toxicity or has adverse effects on function. Specific Aim 3: Determine whether LRP mediated ERK activation is responsible for the tPA induced MMP9 upregulation in vivo. The proposed studies will allow us to better understand the mechanisms of outflow facility regulation by tPA and determine whether an enzymatically inactive variant can be used for chronic therapy of OAG to prevent functional visual loss from the disease. It is thus expected to significantly contribute to the health and well-being of veterans who are known to be disproportionately affected from glaucoma

开角型青光眼（OAG）是一组可导致失明的进行性视神经病变。这是一个 少数民族和退伍军人中严重的健康问题，他们不成比例地受到疾病的影响。 OAG病理学涉及增加的IOP，这是由于房水的流出功能降低。 高IOP增加了青光眼性神经变性的发展和进展的风险， 功能丧失尽管目前的OAG治疗是针对降低IOP，但很少靶向OAG的部位，如果有的话。 流出道组织的病理或增加流出道的便利性。 组织型纤溶酶原激活物（tPA）是一种丝氨酸蛋白酶，在流出道功能中起重要作用 调控我们已经证明，tPA在类固醇诱导的IOP升高中降低，流出道功能降低。 在tPA（PLAT）缺失动物中减少。此外，外源性补充tPA逆转流出功能 在类固醇诱导的青光眼以及tPA无效动物中，IOP降低和IOP升高。我们还 令人惊讶地显示，tPA和酶失活tPA（EI-tPA）可以改善人流出便利性 突变型肌球蛋白转基因动物。 我们在此建议确定使用tPA和EI-tPA作为长期治疗的有效性和安全性， OAG，并阐明通过tPA导致其对流出设施的影响的分子机制。 我们的假设是，在流出道组织中过表达EI-tPA在治疗中是安全有效的 OAG，并导致视力保护。此外，我们假设EI-tPA导致基质 金属蛋白酶9（MMP 9）通过低密度脂蛋白受体相关蛋白（LRP）上调 受体和细胞外信号调节激酶（ERK）信号传导。为了验证这一假设，我们提出了 具体目标如下： 具体目标1：确定tPA或EI-tPA长期治疗是否可用于治疗青光眼 并防止疾病造成的功能损伤。 具体目标2：确定tPA或EI-tPA长期治疗是否会导致视网膜或其他眼睛 毒性或对功能有不良影响。 具体目标3：确定LRP介导的ERK激活是否负责tPA诱导的细胞凋亡。 体内MMP 9上调。 建议的研究将使我们更好地了解流出设施的监管机制， tPA，并确定是否可以将酶失活的变体用于OAG的慢性治疗， 预防疾病导致的功能性视力丧失。因此，预计它将大大有助于健康和 已知受青光眼影响不成比例的退伍军人的福祉