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。它是一个 少数族裔和退伍军人中存在严重的健康问题，他们受到该疾病的影响尤为严重。 OAG 病理涉及眼压升高，这是房水流出功能减少的结果。 高眼压会增加青光眼性神经变性的发生和进展的风险 功能丧失。尽管目前的 OAG 疗法旨在降低 IOP，但很少有针对 OAG 部位的治疗。 流出组织的病理学或增加流出设施。 组织纤溶酶原激活剂 (tPA) 是一种丝氨酸蛋白酶，在流出设施中发挥重要作用 规定。我们已经证明，在类固醇引起的 IOP 升高中，tPA 会降低，并且流出设施会降低 在 tPA (PLAT) 无效的动物中减少。此外，外源性补充 tPA 可逆转流出功能 类固醇诱导的青光眼以及 tPA 缺失动物的眼压降低和升高。我们还有 令人惊讶的是，tPA 和酶无活性 tPA (EI-tPA) 可以改善人体的流出能力 突变肌纤蛋白转基因动物。 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 tPA 对流出设施产生影响的分子机制。 我们的假设是，流出组织中 EI-tPA 的过度表达在治疗中是安全有效的 OAG 并导致视力保留。此外，我们假设 EI-tPA 导致基质 通过低密度脂蛋白受体相关蛋白 (LRP) 上调金属蛋白酶 9 (MMP9) 受体和细胞外信号调节激酶 (ERK) 信号传导。为了检验这个假设，我们提出 以下具体目标： 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 并预防疾病造成的功能损害。 具体目标 2：确定 tPA 或 EI-tPA 的长期治疗是否会导致视网膜或其他眼睛损伤 毒性或对功能有不良影响。 具体目标 3：确定 LRP 介导的 ERK 激活是否是 tPA 诱导的原因 MMP9 体内上调。 拟议的研究将使我们能够更好地理解流出设施监管的机制 tPA 并确定酶失活变体是否可用于 OAG 的慢性治疗 预防疾病引起的功能性视力丧失。因此，预计它将对健康和 已知受青光眼影响尤为严重的退伍军人的健康