Mechanisms underlying endothelin mediated neurodegeneration in glaucoma

内皮素介导的青光眼神经变性的机制

• 批准号: 9767215
• 负责人: RAGHU R KRISHNAMOORTHY
• 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: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767215
• 关键词: ATF2 gene; Animal Model; Apoptosis; Applications Grants; Astrocytes; Attenuated; Axon; Axonal Transport; CREB1 gene; Cell Survival; Clinical Trials; Data; Development; Dose; Electroretinography; Endothelin; Endothelin B Receptor; Endothelin Receptor; Endothelin Receptor Antagonist; Endothelin-1; Endothelin-2; Endothelin-3; Eye; FOS gene; Family; Functional disorder; Glaucoma; Grant; Human; Inner Plexiform Layer; Intervention; JUN gene; Laboratories; MAP Kinase Signaling Pathways; MAPK10 gene; MAPK14 gene; MAPK8 gene; MAPK9 gene; Mediating; Molecular; Mus; N-terminal; Nerve Degeneration; Nerve Fibers; Neurons; Neuroprotective Agents; Ocular Hypertension; Optic Disk; Optic Nerve; Pathology; Pathway interactions; Patients; Pattern; Peptides; Pharmacology; Phosphorylation; Phosphotransferases; Play; Process; Proteins; Rattus; Rattus norvegicus; Receptor Activation; Retina; Retinal Ganglion Cells; Rodent; Rodent Model; Role; Signal Transduction; TP53 gene; Testing; Therapeutic Intervention; Tissues; Viral; Vision; Work; activating transcription factor 1; activating transcription factor 3; axon injury; gene therapy; knock-down; mitogen-activated protein kinase p38; neuroprotection; novel therapeutics; overexpression; pressure; receptor; small hairpin RNA; tomography; transcriptome sequencing; translatome; vector

Project Summary: Endothelin B (ETB) receptors have been shown to be elevated in various ocular tissues in animal models of glaucoma. Our preliminary data suggest that ETA receptors are also increased in retinas of rats with elevated IOP. Previous work from our laboratory showed that many of the deleterious effects of ocular hypertension including optic nerve axonal injury and retinal ganglion cell (RGC) loss are attenuated in ETB receptor-deficient rats. This suggests a causative role of ETB receptors in neurodegeneration. However, the mechanisms underlying endothelin mediated neurodegeneration of the optic nerve and RGCs are not understood. The main hypothesis that antagonism of the endothelin receptors promotes neuroprotection by attenuating the c-Jun N-terminal kinase (JNK) and p38 MAP kinase pathway during ocular hypertension. The current grant application will comprise of the following specific aims: 1) Determine if the endothelin receptors mediate neurodegeneration of RGCs and their axons by activating c-Jun N-terminal kinase (JNK) and p38 MAP kinase signaling pathways in rodents. 2) Elucidate the signaling mechanisms involved in endothelin mediated apoptosis of cultured primary retinal ganglion cells. 3) Investigate if endothelin receptor antagonism is neuroprotective in a rodent model of ocular hypertension. The highlights of this project include a gene therapy intervention using adeno-associated viral knock down of ETA as well as the ETB receptor to determine its neuroprotective effects during ocular hypertension in rats. Another approach proposed in the grant is the use of endothelin receptor antagonists to block endothelin receptors and promote neuroprotection in IOP elevated rats. The project will assess the contribution of endothelin receptors to neurodegeneration and delineate the role of the JNK and p38 MAP kinase pathway in endothelin receptor-mediated neurodegeneration during ocular hypertension in rats. The project will also generate possibilities for molecular as well as pharmacological interventions to block endothelin receptors thereby promote neuroprotection of RGCs and their axons. The basic information gained from these studies would facilitate development of neuroprotective agents for treatment of glaucoma.

项目概要： 内皮素B（ET B）受体已显示在各种眼组织中升高， 青光眼的动物模型。我们的初步数据表明，ETA受体也增加， 在高眼压大鼠的视网膜中。我们实验室以前的工作表明， 高眼压的有害影响包括视神经轴突损伤和视网膜神经节 细胞（RGC）损失在ETB受体缺陷大鼠中减弱。这表明， 神经变性中的ETB受体。然而，内皮素介导的潜在机制 视神经和RGC的神经变性尚不清楚。主要假设 内皮素受体的拮抗作用通过减弱 c-Jun N-末端激酶（JNK）和p38 MAP激酶通路在眼内 高血压目前的拨款申请将包括以下具体目标：1） 确定内皮素受体是否介导RGCs及其轴突的神经变性， 在啮齿类动物中激活c-Jun N-末端激酶（JNK）和p38 MAP激酶信号通路。（二） 阐明内皮素介导细胞凋亡的信号转导机制 原代视网膜神经节细胞3)研究内皮素受体拮抗剂是否具有神经保护作用 在高眼压的啮齿动物模型中。该项目的亮点包括一种基因疗法 使用ETA和ETB受体的腺相关病毒敲低进行干预， 确定其在大鼠高眼压期间的神经保护作用。另一种方法 该基金建议使用内皮素受体拮抗剂来阻断内皮素受体， 对高眼压大鼠有神经保护作用。该项目将评估以下方面的贡献： 内皮素受体对神经退行性变的影响，并阐明JNK和p38 MAP的作用 内皮素受体介导高眼压性神经变性中激酶通路 对大鼠该项目还将产生分子以及药理学的可能性 阻断内皮素受体的干预，从而促进RGC及其受体的神经保护作用。 轴突从这些研究中获得的基本信息将有助于制定 用于治疗青光眼的神经保护剂。