Novel Mechanisms of Subretinal Fibrosis in Age-related Macular Degeneration

年龄相关性黄斑变性视网膜下纤维化的新机制

• 批准号: 10397018
• 负责人: RAM KANNAN
• 金额: $ 35.25万
• 依托单位: DOHENY EYE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397018
• 关键词: Address; Adult; Age; Age related macular degeneration; Angiogenesis Inhibitors; Attention; Behavior; Bioenergetics; Biopolymers; Blindness; Cell Aging; Cells; Cessation of life; Choroidal Neovascularization; Complication; Crystallins; Data; Development; Disease; Drug Kinetics; Elastin; Elderly; Eye; Female; Fibrosis; Generations; Grant; Heat shock proteins; Human; In Vitro; Knowledge; Laser injury; Lasers; Lesion; MADH4 gene; Mitochondria; Modeling; Molecular Weight; Mus; Nonexudative age-related macular degeneration; Oryctolagus cuniculus; Outcome; Oxidative Phosphorylation; Pathogenesis; Pathogenicity; Pathway interactions; Peptides; Pharmaceutical Preparations; Phase; Phenotype; Play; Proteins; Regulation; Retina; Retinal Degeneration; Role; Structure of retinal pigment epithelium; Testing; Time; Translating; Translations; Treatment Efficacy; Tropoelastin; Visual; Visual impairment; Work; aged; bevacizumab; biomaterial compatibility; effective therapy; improved; in vivo; insight; male; mitochondrial dysfunction; mitochondrial metabolism; nanoparticle; new growth; novel; novel therapeutic intervention; novel therapeutics; polypeptide; prevent; senescence; sodium iodate

Project Abstract Age-related macular degeneration (AMD) remains a leading cause of loss-of-vision that necessitates mechanistic studies of disease and the development of new therapeutics. Early AMD progresses to later, blinding forms following one of two divergent pathways: i) Atrophic AMD is associated with degeneration and death of retinal pigment epithelium (RPE); and ii) choroidal neovascularization (CNV) is associated with growth of new vessels under the retina. While there are treatments for CNV using anti-angiogenic drugs, there are no effective treatments for subretinal fibrosis (SRF). SRF is a complication of both end-stage and treated CNV that results in severe to profound visual impairment. To address this complication, our team invented a novel αB-crystallin peptide nanoparticle (αBC-ELP) that markedly inhibits the progression of SRF. Elastin-like polypeptides (ELPs) are high molecular weight biocompatible biopolymers derived from human tropoelastin that retain a biologically-active fragment of the αB-crystallin protein near the retina for extended periods, thus enabling their therapeutic efficacy. As supported by our preliminary data, we hypothesize that αBC-ELP will prevent the progression of SRF compared to controls. We further hypothesize that the inhibitory effect of (αBC-ELP) on SRF decreases the generation of fibrosis-promoting, senescent cells and improves the regulation of mitochondrial metabolism by promoting oxidative phosphorylation. These hypotheses will be tested using the following Specific Aims: Aim #1. Characterize ocular pharmacokinetics of intravitreal αBC- ELP in mouse and rabbit eyes. Aim #2. Characterize SRF and determine effect and time course of αBC-ELP in laser model of CNV. Aim #3. Establish the mechanistic role of senescence cells in progression of SRF and the mechanism of its inhibition by αBC-ELP. Aim #4. Establish the mechanistic role of mitochondrial bioenergetics and mitochondrial SMAD4 in SRF and the mechanism of its inhibition by αBC-ELP.

项目摘要 视网膜相关性黄斑变性（AMD）仍然是视力丧失的主要原因， 疾病的机制研究和新疗法的开发。早期AMD进展到晚期， 遵循两种不同途径之一的致盲形式：i）萎缩性AMD与变性相关， 视网膜色素上皮（RPE）死亡;和ii）脉络膜新生血管（CNV）与生长相关 视网膜下的新生血管虽然有使用抗血管生成药物治疗CNV，但没有 视网膜下纤维化（SRF）的有效治疗。SRF是终末期和治疗后CNV的并发症 会导致严重的视觉障碍为了解决这一复杂问题，我们的团队发明了一种新的 α B-晶状体蛋白肽纳米粒（αBC-ELP），可显著抑制SRF的进展。蛋白样 多肽（ELP）是来源于人原弹性蛋白的高分子量生物相容性生物聚合物 在视网膜附近保留α B-晶状体蛋白的生物活性片段， 使其具有治疗功效。根据我们的初步数据，我们假设αBC-ELP将 与对照组相比，预防SRF的进展。我们进一步假设， （αBC-ELP）对SRF的作用减少了促纤维化、衰老细胞的产生，并改善了SRF的抗纤维化能力。 通过促进氧化磷酸化调节线粒体代谢。这些假设将是 使用以下特定目标进行测试：目标#1。表征玻璃体内αBC的眼部药代动力学- ELP在小鼠和兔眼中。目标2。表征SRF并确定αBC-ELP的作用和时间过程 CNV的激光模型目标3。确定衰老细胞在SRF进展中的机制作用， 探讨αBC-ELP抑制其作用的机制。目标4。建立线粒体的机械作用 SRF中的生物能量学和线粒体SMAD 4以及αBC-ELP对其的抑制机制。