EGF Receptor and Notch Signaling in the Pathogenesis of Menetrier's Disease

项目总结/摘要 梅内特里尔病是一种罕见的获得性低蛋白血症性肥大性胃病。患者表现为 一系列进行性体征和症状，包括严重腹痛、持续恶心和 呕吐、外周水肿（由于胃粘膜蛋白质损失）和无氯血症（由于胃粘膜蛋白质损失）。 产酸壁细胞），沿着胃癌风险增加。直到最近，胃切除术 是唯一的治疗方法我的导师（Bob Coffey）的实验室发现EGFR信号的增加 在梅内特里尔病的发病机制中的作用。EGFR配体，转化生长因子-α（TGF-α）， 在梅内特里尔病患者的胃粘膜中过度表达，以及过度表达TGF-β 1的转基因小鼠， α在胃表型的许多特点梅内特里尔的疾病。此外，EGFR中和 西妥昔单抗是治疗这种疾病的第一种有效的药物，所有7名患者都接受了治疗。 临床试验显示客观改善。一名患者被治愈，但其他六名患者最终需要 胃切除术，因此需要改进的疗法。根据我在科菲实验室的独立工作，我们有 发现Notch信号被上调，并且是梅内特里尔病中EGFR信号的下游 患者和MT-TGF-α小鼠。初步数据表明，联合阻断Notch和EGFR信号传导 在治疗MT-TGF-α小鼠中比单独的EGFR阻断更有效。为了研究Notch信号通路在 在Ménétrier病中，我们将利用MT-TGF-α小鼠，一种新的内源性EGFR报告细胞系EgfrEmeraldGFP， 第一个针对小鼠EGFR的中和抗体，P1 X/P2 X。目标1将检查快速损失的原因 梅内特里尔病的壁细胞初步数据表明，主细胞中的EGFR信号传导增加了 以旁分泌方式减少壁细胞数量的锯齿状1。目标2将研究大规模 Ménétrier病的小凹增生。在目标3中，我们将通过以下方式优化梅内特里尔病的治疗方法： 将P1 X/P2 X和Notch抑制剂、γ-分泌酶抑制剂二苯并氮杂卓（DBZ）组合，在体内使用MT- TGF-α小鼠。如果我们能证明这种组合在来源于胃粘膜的胃类器官中的治疗效果， 梅内特里尔病患者，我们将考虑推进到一项优化方案的临床试验。 获得此K 08奖将提供所需的保护时间，指导，培训和支持， 实现了我成为一名独立的医学科学家的目标。这项研究建议非常适合NIDDK 因为它涉及消化系统疾病的发病机理和治疗。范德比尔特提供了基础和临床 为实现本建议的目标所需的资源。我的导师和共同导师在这方面有专长 并有一个成功的指导记录，我已经组建了一个咨询委员会， 补充专业知识。我还制定了职业发展计划，以获得所需的技能， 确保我成功地建立一个独立的研究计划，完成这个奖项。

PROJECT SUMMARY/ABSTRACT Ménétrier’s disease is an uncommon acquired hypoproteinemic hypertrophic gastropathy. Patients present with a constellation of progressive signs and symptoms that include severe abdominal pain, unremitting nausea and vomiting, peripheral edema (due to loss of protein across the gastric mucosa) and achlorhydria (due to loss of acid-producing parietal cells), along with an increased risk of gastric cancer. Until recently, gastrectomy has been the only therapeutic option. The lab of my mentor (Bob Coffey) has implicated increased EGFR signaling in the pathogenesis of Ménétrier’s disease. The EGFR ligand, transforming growth factor-α (TGF-α) is overexpressed in the gastric mucosa of Ménétrier’s disease patients, and transgenic mice that overexpress TGF- α in the stomach phenocopy many of the features of Ménétrier’s disease. Moreover, the EGFR neutralizing antibody, cetuximab, is the first effective medical therapy for this disorder with all seven patients treated in a clinical trial showed objective improvement. One patient was cured but the other six ultimately required gastrectomy, thus improved therapies are needed. From my independent work in the Coffey lab, we have discovered that Notch signaling is upregulated and is downstream of EGFR signaling in Ménétrier’s disease patients and MT-TGF-α mice. Preliminary data indicates that combined blockade of Notch and EGFR signaling is more effective in treating MT-TGF-α mice than EGFR blockade alone. To investigate the role of Notch signaling in Ménétrier’s disease, we will utilize MT-TGF-α mice, a novel endogenous EGFR reporter line, EgfrEmeraldGFP and the first neutralizing antibodies to mouse EGFR, P1X/P2X. Aim 1 will examine the cause of the rapid loss of parietal cells in Ménétrier’s disease. Preliminary data suggest that EGFR signaling in chief cells increases the Jagged1 that acts in a paracrine manner to reduce parietal cell number. Aim 2 will examine the cause of massive foveolar hyperplasia in Ménétrier’s disease. In Aim 3, we will optimize therapeutics for Ménétrier’s disease by combining P1X/P2X and a Notch inhibitor, the γ-secretase inhibitor, dibenzazepine (DBZ), in vivo using MT- TGF-α mice. If we can show the therapeutic efficacy of this combination in gastric organoids derived from Ménétrier’s disease patients, we will consider advancing to a clinical trial with an optimized regimen. Receiving this K08 award would provide the protected time, mentorship, training and support required for achieving my goal to be an independent physician-scientist. This research proposal is well suited for the NIDDK as it relates to the pathogenesis and treatment of a digestive disorder. Vanderbilt provides the basic and clinical resources needed to carry out the aims of this proposal. My mentor and co-mentor have expertise in this area and have a proven track record of successful mentoring, and I have assembled an advisory committee with complementary expertise. I also have delineated a career development plan to acquire the required skills to ensure my success in establishing an independent research program by the completion of this award.