Regulation of the double-stranded RNA (dsRNA) response in gastric metaplasia and dysplasia

项目总结/摘要 胃上皮化生是胃癌进展过程中的一个重要的癌前事件， 是全球癌症相关死亡的主要原因。胃上皮化生的程度是一个显著的 胃癌发病率指标。虽然我们认识到化生上皮的特征是 分泌酸的壁细胞的损失和酶原主细胞向增殖表型的重编程， 我们仍然缺乏对胃上皮在化生期间如何调节细胞应激的机制的理解 以及哪些信号通路决定了癌症的进展。 我的初步发现确定了对双链RNA（dsRNA）的反应是最高的。 在小鼠中两种不同的化生诱导模型中，dsRNA信号转导通路上调，这表明dsRNA信号转导 代表了保守的化生途径另外，我的独立分析发现， 反应是人类胃癌中最显著下调的途径之一。虽然 dsRNA反应经常在病毒感染的背景下进行研究，这些发现表明， dsRNA应答的上皮调节对胃化生和肿瘤发生至关重要。 本申请提出定义dsRNA应答的调节如何影响细胞的免疫应答。 胃上皮化生的建立和向异型增生的进展。作为我第一个目标的一部分，我将决定 使用已建立的胃类器官和胃上皮细胞， 体内模型。更具体地说，我将描述dsRNA反应的失调如何主要 上皮细胞是化生反应的关键上皮细胞系，影响胃上皮化生的发展， vivo.这将依赖于新开发的小鼠模型，其中dsRNA信号传导的关键调节因子ADAR 1可以 从主细胞中有条件地、有针对性地删除。沿着这些线，一个类似的老鼠模型，我 发现壁细胞中ADAR 1的特异性缺失导致胃发育不良，这意味着 dsRNA信号传导在胃肿瘤发生中的谱系特异性作用。我的第二个目标将研究 通过转录表征Adar 1缺陷型壁细胞在不同条件下的壁细胞命运中的dsRNA信号传导 壁细胞发育的各个阶段。此外，该目标将定义Tnfrsf 11b的作用，Tnfrsf 11b是最重要的基因之一。 在我的胃发育不良小鼠模型中发现了上调的基因， 胃癌，在促进发育不良的环境。本申请中提出的实验被告知 我的K 08奖的一些目标，但他们将研究新的实验方法， 补充和扩展这些假设。更重要的是，这些发现将提供新的机制， 深入了解dsRNA信号传导对胃肿瘤发生的贡献，并可能导致新的诊断方法。 和治疗替代品。

PROJECT SUMMARY/ABSTRACT Gastric metaplasia represents a critical pre-neoplastic event in the progression to gastric cancer, one of the leading causes of cancer-related deaths worldwide. The extent of gastric metaplasia is a significant indicator of gastric cancer incidence. While we recognize that metaplastic epithelium is characterized by the loss of acid-secreting parietal cells and a reprogramming of zymogenic chief cells to a proliferative phenotype, we still lack a mechanistic understanding of how gastric epithelium regulates cellular stress during metaplasia and what signaling pathways determine the progression to cancer. My preliminary findings identified the response to double-stranded RNA (dsRNA) as the most highly upregulated pathway across two distinct metaplasia-inducing models in mice, suggesting that dsRNA signaling represents a conserved, metaplastic pathway. In addition, my independent analysis found that the dsRNA response was one of the most significantly downregulated pathways in human gastric cancer. Though the dsRNA response has often been studied in the context of viral infection, these findings would suggest that the epithelial regulation of the dsRNA response is crucial to gastric metaplasia and tumorigenesis. This application proposes to define how the regulation of the dsRNA response affects the establishment of gastric metaplasia and the progression to dysplasia. As part of my first Aim, I will determine the necessity and sufficiency of dsRNA signaling in gastric metaplasia, using established gastric organoid and in vivo models. More specifically, I will characterize how the dysregulation of the dsRNA response in chief cells, an epithelial lineage critical to the metaplastic response, affects the development of gastric metaplasia in vivo. This will rely on a newly developed murine model where a key regulator of dsRNA signaling, ADAR1, can be conditionally and specifically deleted from chief cells. Along those lines, a similar mouse model that I developed found that specific deletion of ADAR1 from parietal cells resulted in gastric dysplasia, implying lineage-specific effects of dsRNA signaling in gastric tumorigenesis. My second Aim will examine the role of dsRNA signaling in parietal cell fate by transcriptionally characterizing Adar1-deficient parietal cells at distinct stages of parietal cell development. In addition, this Aim will define the role of Tnfrsf11b, one of the most highly upregulated genes in my murine model of gastric dysplasia and a gene found to be upregulated in human gastric cancer, in promoting the dysplastic milieu. The experiments proposed in this application are informed by some of the objectives from my K08 award, but they will investigate new experimental approaches that will complement and expand on these hypotheses. More importantly, these findings will offer new mechanistic insight into the contribution of dsRNA signaling to gastric tumorigenesis and potentially lead to new diagnostic and therapeutic alternatives.