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

项目摘要/摘要 梅尼特里尔病是一种罕见的获得性低蛋白血症肥厚性胃病。出席的患者有 一系列进行性体征和症状，包括剧烈的腹痛，持续的恶心和 呕吐、外周水肿(由于胃粘膜上的蛋白质丢失)和酸痛(由于胃粘膜蛋白丢失) 产酸的壁细胞)，以及患胃癌的风险增加。直到最近，胃切除术还在 是唯一的治疗选择。我的导师(鲍勃·科菲)的实验室发现EGFR信号增加 在梅内特里尔病的发病机制中起重要作用。其配体转化生长因子-α(转化生长因子-α)是 Ménétrier病患者的胃粘膜中过表达，以及过表达转化生长因子-1的转基因小鼠 胃中的α表现出梅恩特里尔病的许多特征。此外，EGFR的中和 抗体西妥昔单抗是治疗这种疾病的第一种有效的药物疗法，所有七名患者都在 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治疗。 胃切除术，因此需要改进治疗方法。从我在科菲实验室的独立工作中，我们有 Ménétrier病中Notch信号上调且位于EGFR信号下游 患者和MT-转化生长因子-α小鼠。初步数据显示，Notch和EGFR信号的联合阻断 在治疗MT-转化生长因子-α小鼠方面比单独阻断表皮生长因子受体更有效。研究Notch信号转导途径的作用 在Ménétrier病中，我们将利用MT-转化生长因子-α小鼠，一个新的内源性EGFR报告系EgfrEmeraldGFP和 首次发现了针对小鼠EGFR的中和抗体P1X/P2X。目标1将检查快速损失的原因 梅尼特里尔病的壁细胞。初步数据表明，主细胞中的EGFR信号增加了 以旁分泌的方式减少壁细胞数量的。目标2将研究大规模爆炸的原因 梅尼特里尔病的黄斑中心凹增生症。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 结合P1X/P2X和Notch抑制剂，γ分泌酶抑制剂二苯扎西平(DBZ)在体内使用MT- 转化生长因子-α小鼠。如果我们能证明这种组合对来自于 对于Ménétrier病患者，我们将考虑推进优化方案的临床试验。 获得K08奖将提供受保护的时间、指导、培训和所需的支持 实现了我的目标，成为一名独立的内科科学家。该研究方案非常适合NIDDK 因为它与消化系统疾病的发病机制和治疗有关。范德比尔特提供了基础和临床 实现这项提案的目标所需的资源。我的导师和合作导师在这方面有专长 并且有成功的指导记录，我已经组建了一个咨询委员会， 互补的专业知识。我还制定了一项职业发展计划，以获得必要的技能 通过完成这一奖项，确保我成功地建立了一个独立的研究项目。

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.