Trained immunity in the retina and its influence on retinal degenerative disorders

视网膜的训练免疫力及其对视网膜退行性疾病的影响

• 批准号: 459037870
• 负责人: Professor Dr. Thomas Langmann
• 金额: --
• 依托单位: Zentrum für Augenheilkunde
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/459037870?language=en
• 关键词: Trained; immunity; retina; its; influence

We and others have shown that when retinal microglia become pathologically activated by sustained stimulation, they release inflammatory mediators which are detrimental to vision-producing retinal neurons. However, it is not yet clear which molecular mechanisms underpin these exaggerated responses. Our preliminary data in the laser model of choroidal neovascularization indicates the presence of innate immune memory in the retina. Therefore, the goal of this study is to further investigate the role of trained immunity in the development of maladaptive inflammatory responses in the mouse retina with the aim of better understanding the immunological basis of retinal degenerative disorders. The proposed study is subdivided into two specific aims. In specific aim 1, we will endeavor to determine whether immunological memory can be imprinted in the retina by in vivo exposure to a metabolic or microbial microglial priming stimulus (peripheral or local application) to generate an enhanced inflammatory response to subsequent genetically or experimentally induced retinal damage. We will apply in vivo imaging, microglia histomorphometry and three different high throughput sequencing methods (RNA-seq, ATAC-Seq, ChIP-seq) in two different mouse models that mimic some important neuropathological features of human retinitis pigmentosa and atrophic age-related macular degeneration and determine how immune memory in the retina can modify disease pathogenesis. In specific aim 2, we will perform a proof-of concept study and determine whether blocking immunological memory in retinal microglia using cell-specific knockout of transforming growth factor-activated kinase 1 (Tak1), a key epigenetic pathway for immune training, can positively influence disease outcome in the two mouse models of retinal pathology. Successful completion of this work will uncover mechanisms governing immune cell activation in the retina and explore the potential interactions between long-term exposure to environmental and lifestyle stressors that may contribute to the development and progression of retinal pathologies. Importantly, completing the proposed work holds promise to identify critical mediators of trained immunity in the retina and pave the way towards new strategies for mitigating retinal pathologies with an inflammatory component.

我们和其他人已经表明，当视网膜小胶质细胞被持续刺激病理激活时，它们会释放对产生视觉的视网膜神经元有害的炎症介质。然而，目前尚不清楚是哪些分子机制支持这些夸张的反应。我们在脉络膜新生血管激光模型中的初步数据表明视网膜中存在先天免疫记忆。因此，本研究的目的是进一步研究训练免疫在小鼠视网膜适应不良炎症反应发展中的作用，目的是更好地了解视网膜退行性疾病的免疫学基础。拟议的研究分为两个具体目标。在具体目标1中，我们将奋进确定免疫记忆是否可以通过体内暴露于代谢或微生物小胶质细胞引发刺激（外周或局部应用）而在视网膜中印迹，以产生对随后的遗传或实验诱导的视网膜损伤的增强的炎症反应。我们将在两种不同的小鼠模型中应用体内成像，小胶质细胞组织形态计量学和三种不同的高通量测序方法（RNA-seq，ATAC-Seq，ChIP-seq），模拟人类视网膜色素变性和萎缩性年龄相关性黄斑变性的一些重要神经病理学特征，并确定视网膜中的免疫记忆如何改变疾病的发病机制。在具体目标2中，我们将进行一项概念验证研究，并确定是否使用转化生长因子激活激酶1（Tak 1）的细胞特异性敲除来阻断视网膜小胶质细胞中的免疫记忆，这是免疫训练的关键表观遗传途径，可以积极影响两种视网膜病理学小鼠模型的疾病结果。这项工作的成功完成将揭示视网膜中免疫细胞激活的机制，并探索长期暴露于环境和生活方式压力之间的潜在相互作用，这些压力可能有助于视网膜病变的发展和进展。重要的是，完成拟议的工作有望确定视网膜中训练免疫的关键介质，并为减轻具有炎症成分的视网膜病变的新策略铺平道路。