Mntrier?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 Mntrier?s disease. The EGFR ligand, transforming growth factor-? (TGF-?) is overexpressed in the gastric mucosa of Mntrier?s disease patients, and transgenic mice that overexpress TGF- ? in the stomach phenocopy many of the features of Mntrier?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 Mntrier?s disease patients and MT-TGF-? mice. Preliminary data indicates that combined blockade of Notch and EGFR signaling is more effective in treating MT-TGF-? mice than EGFR blockade alone. To investigate the role of Notch signaling in Mntrier?s disease, we will utilize MT-TGF-? 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 Mntrier?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 Mntrier?s disease.
In Aim 3, we will optimize therapeutics for Mntrier?s disease by combining P1X/P2X and a Notch inhibitor, the ?-secretase inhibitor, dibenzazepine (DBZ), in vivo using MT- TGF-? mice. If we can show the therapeutic efficacy of this combination in gastric organoids derived from Mntrier?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.
Mntrier?s disease is an acquired premalignant hypertrophic gastropathy caused by EGF receptor (EGFR) signaling activation in which the EGFR neutralizing monoclonal antibody, cetuximab, is the first effective medical therapy. My identification of Notch signaling downstream of EGFR signaling in Mntrier?s disease has led to the design of present studies that will dissect the role of EGFR and Notch signaling in two cardinal features of the disease (loss of parietal cells and foveolar hyperplasia) and optimize pharmacological blockade of EGFR and Notch signaling to improve the treatment of affected individuals. The results of this study will enlighten the detailed pathogenesis of Mntrier?s disease and lead to the development of clinical trials.
