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

梅内特里耶病发病机制中的 EGF 受体和 Notch 信号传导

• 批准号: 10614947
• 负责人: Won Jae Huh
• 金额: $ 16.61万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614947
• 关键词: Abdominal Pain; Achlorhydria; Acids; Advisory Committees; Affect; Antibodies; Area; Atrophic; Award; Cell Count; Cell Differentiation process; Cells; Cetuximab; Chief Cell; Clinical; Clinical Trials; Data; Development Plans; Digestive System Disorders; Disease; Distal; ES01; Edema; Ensure; Epidermal Growth Factor Receptor; Event; Formalin; Gastrectomy; Gastric Parietal Cells; Gastric mucosa; Generations; Genetic; Gland; Goals; Hand; Heavy Metals; Hyperplasia; Hypertrophic Gastritis; Hypoproteinemia; Immunofluorescence Immunologic; Individual; Knock-out; Knockout Mice; Label; Ligands; Medical; Mentors; Mentorship; Microscopic; Molecular; Mucous Membrane; Mucous body substance; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nausea and Vomiting; P2X-receptor; Paraffin Embedding; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral; Phenocopy; Physicians; Proliferating; Proteins; Receptor Activation; Receptor Signaling; Regimen; Reporter; Research; Research Proposals; Resources; Risk; Role; Scientist; Signal Transduction; Signs and Symptoms; Stains; Stomach; Surface; Symptoms; Therapeutic; Time; Training; Transforming Growth Factor alpha; Transgenic Mice; Treatment Efficacy; Visualization; Western Blotting; Woman; Work; career development; cell type; clinical development; design; gamma secretase; gastric fundus; gastric organoids; immunoreactivity; improved; in vivo; inhibitor; malignant stomach neoplasm; men; middle age; neutralizing antibody; neutralizing monoclonal antibodies; notch protein; novel; overexpression; paracrine; pharmacologic; premalignant; progenitor; programs; receptor; single-cell RNA sequencing; skills; stem; stem cells; success; therapeutically effective; tool

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.

项目总结/文摘