Elastase and Elastin Peptide Activity in Age-Related Macular Degeneration

长期目标是了解眼睛中补体信号的基本基础，以及如何 这一过程中的错误调控会导致病理，最终有助于治疗性AP的发展。 治疗毁灭性致盲疾病的方法。BRM是一种五层细胞外基质隔室，包含 中间弹力层(含有弹性蛋白，EL)。这种电致发光的厚度和完整性更薄，更不丰富 在黄斑部比在周边；这种差异在早期AMD和活动性脉络膜中更为严重 新生血管(CNV)。AMD患者血清EL多肽和抗EL抗体水平升高；以及 EL多肽可以增加脉络膜内皮细胞的迁移，总体上表明EL的异常 动态平衡在AMD中起着一定的作用。我们已经确定了一种烟雾诱导的眼部病理的小鼠模型。 (SIOP)C57BL/6J小鼠。这些小鼠的血清中抗EL抗体(Abs，IgG2a)水平升高， 并且显示出弹性层的完整性的完全丧失。相反，氧化EL免疫的小鼠 (新表位)与免疫者相比，BRM患者会出现更严重的视力损失和病理 用对照EL(自身蛋白)。我们遵循我们的总体假设，即年龄和/或压力依赖 弹性酶活性增加导致弹性蛋白降解和协调产生(抗)α-弹性蛋白抗体 是AMD的早期事件。我们进一步假设，α-弹性蛋白抗体与Fc-γ受体结合后会触发抗体- 依赖细胞介导的细胞毒性，加剧AMD的病理，这一机制被COM-1放大。 依赖于补体的细胞毒性。此外，我们还建议，α-1抗胰蛋白酶(A1AT)，一种内源性弹性蛋白酶 作为一种潜在的早期AMD治疗方法，可用于保持BRM的完整性。三个具体目标是 旨在确定抗弹性蛋白抗体在小鼠BRM病理模型中的参与，以及 第二，验证A1-AT降低小鼠和人的病理生物学的预测，将A1-AT用于Thera-AT- 小鼠模型的临床用途和分析MarketScan数据库中A1-AT的使用和AMD的发病。 这一想法的新奇之处在于，弹性蛋白酶的活性会导致结构性病变(弹性蛋白丢失，在... 燃烧)，这是非常创新的，现有的弹性蛋白酶抑制剂将测试其能力预- 为BRM诚信服务，作为一种治疗范例，在过程的早期减缓疾病的进展。

The long-term goal is to understand the fundamental basis of complement signaling in the eye, and how misregulation in this process leads to pathology, to ultimately aid in the development of therapeutic ap- proaches for devastating blinding diseases. BrM, a pentalaminar extracellular matrix compartment, contains a middle elastic layer (contains elastin, EL). Thickness and integrity of this EL is thinner and less abundant in the macula than in the periphery; a discrepancy that is more severe in early AMD and active choroidal neovascularization (CNV). AMD patients have elevated serum EL-peptide and anti-EL antibody levels; and EL-peptides can increase choroidal endothelial cell migration, overall suggesting that abnormalities in EL homeostasis play a role in AMD. We have characterized a mouse model of smoke-induced ocular pathology (SIOP) in C57BL/6J mice. These mice exhibit increased serum levels of anti-EL antibodies (Abs, IgG2a), and show a complete loss of integrity of the elastic layer. Conversely, mice immunized with oxidized EL (neoepitope) develop more severe vision loss and pathology in BrM when compared to those immunized with control EL (self-protein). We are guided by our overall hypothesis that age- and/or stress-dependent increase in elastase activity leading to elastin degradation and coordinated production of (anti) α-elastin Abs are early events in AMD. We further hypothesize that α-elastin Abs binding to FcγRs trigger antibody- dependent cell-mediated cytotoxicity, exacerbating AMD pathology, a mechanism that is amplified by com- plement-dependent cytotoxicity. Also, we suggest that alpha-1 antitrypsin (A1AT), an endogenous elastase inhibitor, can be utilized to retain BrM integrity as a potential early AMD therapy. Three specific aims are designed to determine the involvement of antibodies against elastin in BrM pathology in mouse models, and second to test the prediction that A1-AT reduces pathobiology in mouse and man, using A1-AT for thera- peutic purposes in mouse models and analyzing the MarketScan Database for A1-AT use and AMD onset. The novelty of the idea is that elastase activity results in structural pathological changes (elastin loss, in- flammation), and it is highly innovative that an existing elastase inhibitor will be tested for its ability to pre- serve BrM integrity, as a treatment paradigm to slow down the progression of disease early in the process.