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

项目摘要/摘要 胃化生是进展为胃癌的关键癌前事件，其中之一 全球癌症相关死亡的主要原因。胃化生的程度是一个显著的 胃癌发病率的指标。虽然我们认识到化生上皮的特征是 分泌酸性的壁细胞的丧失和产酶主细胞重新编程为增殖表型， 我们仍然缺乏对胃上皮如何在化生过程中调节细胞应激的机械性了解。 以及哪些信号通路决定了癌症的进展。 我的初步发现发现，对双链RNA(DsRNA)的反应是最高的 在小鼠两种不同的化生诱导模型中上调通路，提示dsRNA信号转导 代表了一种保守的化生途径。此外，我的独立分析发现，dsRNA 在人类胃癌中，反应是最显著下调的途径之一。虽然 DsRNA反应通常是在病毒感染的背景下研究的，这些发现表明 上皮细胞对dsRNA反应的调节在胃化生和肿瘤发生中起着至关重要的作用。 此应用程序建议定义dsRNA响应的调节如何影响 胃化生的建立和异型增生的进展。作为我第一个目标的一部分，我将决定 胃化生中dsRNA信号转导的必要性和充分性 活体模型。更具体地说，我将描述dsRNA反应的失调是如何 细胞，一种对化生反应至关重要的上皮细胞，影响胃化生的发展。 活着。这将依赖于一种新开发的小鼠模型，在该模型中，dsRNA信号的关键调节因子ADAR1可以 有条件地和具体地从主要单元格中删除。沿着这些思路，一个类似的老鼠模型，我 研究人员发现，壁细胞中ADAR1的特异性缺失会导致胃不典型增生，这意味着 DsRNA信号在胃肿瘤发生中的谱系特异性作用。我的第二个目标是考察 通过在不同的不同时期对ADAR1缺陷的壁细胞进行转录表征，dsRNA在壁细胞命运中的信号转导 壁细胞发育的各个阶段。此外，这一目标将定义Tnfrsf11b的作用，它是最高级别的 在我的胃异型增生小鼠模型中上调的基因和在人类中发现上调的基因 胃癌，在促进发育不良的环境中起作用。在本申请中提出的实验被告知 通过我的K08奖中的一些目标，但他们将研究新的实验方法， 对这些假设进行补充和扩展。更重要的是，这些发现将提供新的机制 洞察dsRNA信号在胃肿瘤发生中的作用并可能导致新的诊断 和治疗的替代方案。

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.