Novel Mechanisms of Subretinal Fibrosis in Age-related Macular Degeneration

项目摘要 老年性黄斑变性(AMD)仍然是导致视力丧失的主要原因，需要 疾病的机制研究和新疗法的发展。早期AMD进展到较晚， 致盲形式遵循两种不同的途径之一：i)萎缩性AMD与退行性和 视网膜色素上皮(RPE)的死亡；以及II)脉络膜新生血管(CNV)与生长相关 视网膜下的新血管。虽然有使用抗血管生成药物治疗CNV的方法，但没有 视网膜下纤维化(SRF)的有效治疗。SRF是终末期CNV和治疗后CNV的并发症 这会导致严重到严重的视力障碍。为了解决这种复杂性，我们的团队发明了一种新颖的 αB-晶体蛋白多肽纳米粒(αBC-ELP)可显著抑制SRF的进展。类弹力蛋白 多肽(Elps)是来源于人原弹性蛋白的高相对分子质量生物相容性生物聚合物。 在视网膜附近长时间保留具有生物活性的αB-晶状体蛋白片段，因此 使他们的治疗效果。根据我们的初步数据，我们假设αBC-ELP将 与对照组相比，防止SRF的进展。我们进一步假设，它的抑制作用 (αBC-ELP)可减少促纤维化、衰老细胞的产生，并改善 通过促进氧化磷酸化来调节线粒体代谢。这些假设将是 使用以下特定目标进行测试：目的1.表征玻璃体内αBC的眼内药代动力学 小鼠和兔眼的ELP。目的#2.测定αBC-ELP的疗效和时程 在CNV的激光模型中。目的#3.建立衰老细胞在SRF进展中的机制作用 探讨了αBC-ELP对其抑制作用的机制。目标#4.建立线粒体的机械作用 αBC-ELP抑制SRF中生物能量学和线粒体smad4的作用机制。

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.