An Experimental Approach to Maculopathy

项目摘要 对萎缩性年龄相关性黄斑变性（AMD）的基本机制进行了深入研究 通过翻译这项工作来建立新的疗法。早期AMD进展为晚期致盲形式， 遵循两种不同途径之一的疾病;萎缩性AMD或地图状萎缩（GA）与 视网膜色素上皮细胞（RPE）进行性衰老和死亡，而脉络膜 新生血管形成（CNV）与视网膜下新血管的生长有关。在上一个资助期内 我们的假设得到了有力的支持，即骨形态发生蛋白-4的表达增加， RPE中的BMP-4诱导了萎缩性AMD的特征，并抑制了CNV;因此介导了 “分子开关”决定了患者发展为哪种晚期形式的AMD。一个主要的反应， RPE中BMP 4表达的增加是分子伴侣aB晶体蛋白的蛋白表达的上调。我们 假设在早期AMD中，BMP 4表达增加导致RPE衰老和一种新的反应性 神经保护反应与来自RPE的aB晶体蛋白表达增加;然而，作为疾病 当这种反应进展时，这种反应被压倒，并且进一步持续的氧化应激导致进展为GA。 然后，我们假设具有伴侣活性的aB stack衍生的寡肽可以提供类似的功能。 保护RPE免受氧化应激和其他损伤，并且可以选择性地转运到RPE中。 此外，新型aB晶体蛋白肽纳米颗粒可以被组装和优化以有效地拯救 在培养物中以及在具有GA特征的多种鼠模型中的RPE功能障碍。这项工作是高度 因为目前没有有效的治疗GA的方法。假设将使用 具体目标：目标#1。确定分子、细胞和功能的相互关系 RPE中BMP 4和aB晶体蛋白之间的关系以及氧化应激对这些过程的影响。目标二。 开发和优化aB晶体蛋白肽纳米颗粒，抑制RPE中各种形式的应激作用 培养的细胞。目标3。测定aB晶体蛋白肽纳米粒的药代动力学， 眼内或全身递送，并确定这些纳米颗粒抑制肿瘤进展的能力。 在具有GA特征的多种鼠模型中的疾病。

Project Abstract Continued studies on basic mechanisms of atrophic age related macular degeneration (AMD) are proposed with translation of this work to establish novel therapies. Early AMD progresses to late blinding forms of the disease by following one of two divergent pathways; atrophic AMD or geographic atrophy (GA) is associated with progressive senescence and death of the retinal pigment epithelium (RPE), while choroidal neovascularization (CNV) is associated with growth of new vessels under the retina. In the last grant period we developed strong support for our hypothesis that increased expression of bone morphogenetic protein-4 (BMP4) in RPE induces features characteristic of atrophic AMD, and inhibits CNV; thus mediating a "molecular switch" that determines which late form of AMD a patient develops. One of the major responses to increased BMP4 expression in RPE is upregulated protein expression of the chaperone aB crystallin. We hypothesize that in early AMD, increased BMP4 expression leads to RPE senescence and a novel reactive neuroprotective response with increased expression of aB crystallin from RPE; however as disease progresses, this response is overwhelmed and further sustained oxidative stress results in progression to GA. We then hypothesize that aB crystallin-derived oligopeptides with chaperone activity can provide similar protection of RPE from oxidative stress and other injuries and can be selectively transported into the RPE. Furthermore, novel aB crystallin peptide nanoparticles can be assembled and optimized to effectively rescue dysfunctional RPE in culture, and in multiple murine models with features of GA. This work is highly significant since there is currently no effective therapy for GA. The hypotheses will be tested using the following Specific Aims: Aim #1. Determine the molecular, cellular, and functional inter-relationships between BMP4 and aB crystallin in RPE and the effect of oxidative stress on these processes. Aim # 2. Develop and optimize aB crystallin peptide nanoparticles that inhibit effects of various forms of stress in RPE cells grown in culture. Aim # 3. Determine the pharmacokinetics of aB crystallin peptide nanoparticles after intraocular or systemic delivery and determine the ability of these nanoparticles to inhibit progression of disease in multiple murine models with features of GA .