The role of Hedgehog Signaling in gastric tissue homeostasis and disease

Hedgehog 信号传导在胃组织稳态和疾病中的作用

• 批准号: 8423382
• 负责人: Yana Zavros
• 金额: $ 31.78万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423382
• 关键词: Acids; Adoptive Transfer; Adult; Animals; Apical; Atrophic; Atrophic Gastritis; Bacterial Infections; Biological Assay; Biological Markers; Biology; Cancer Diagnostics; Cancer Etiology; Cancerous; Cell Culture Techniques; Cell Differentiation process; Cell Lineage; Cell physiology; Cell-Cell Adhesion; Cells; Cessation of life; Chronic; Data; Development; Diagnosis; Differentiation and Growth; Disease; Embryonic Development; Epithelial; Epithelial Cells; Epithelium; Erinaceidae; Event; Gastric Parietal Cells; Gastric Tissue; Gastritis; Gastrointestinal tract structure; Gland; Goals; Healed; Health; Helicobacter Infections; Helicobacter pylori; Homeostasis; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Laboratories; Left; Lesion; Link; Maintenance; Malignant Neoplasms; Metaplasia; Metaplastic; Molecular; Morphology; Mucous body substance; Mus; Natural regeneration; Neoplasms; Normal Cell; Organ; Outcome; Parietal; Pathogenesis; Patients; Pattern; Play; Prevention; Process; Production; Public Health; Publishing; Research; Role; Sonic hedgehog protein; Splenocyte; Staging; Stomach; T-Lymphocyte; Tamoxifen; Tars; Testing; Therapeutic Intervention; Tight Junctions; Time; Tissues; Tube; Ulcer; Work; base; carcinogenesis; chemokine; cytokine; epithelial to mesenchymal transition; gastric cancer prevention; healing; in vivo; innovation; malignant stomach neoplasm; morphogens; mouse model; mutant; neoplastic; novel; novel strategies; prevent; prognostic; public health relevance; response; smoothened signaling pathway; therapeutic target

DESCRIPTION (provided by applicant): During the progression of the inflamed stomach to gastric cancer, parietal cells fail to secrete acid and are re- placed by metaplastic mucous-secreting cells, a process called gastric atrophy. Compelling evidence shows that inflammation, typically caused by Helicobacter pylori (H. pylori), precedes atrophy. Although atrophy itself is a reliable indicator of pre-neoplastic changes in the stomach, the pathogenesis for the development of this pre-cancerous lesion is largely unknown. Parietal cells secrete numerous factors that modulate the growth and differentiation of the gastric epithelium. One favored explanation linking inflammation and progression to atro- phy is due to the loss of these factors. The Sonic Hedgehog (Shh) signaling pathway is one of the main morphogens expressed in stomach although the mechanism by which Shh regulates gastric epithelial cell dif- ferentiation is unclear. Shh is also a known regulator of cytokine and chemokine production, but its role in the development of H. pylori-induced gastritis has not been investigated. Our long-term goal is to understand the pathogenesis of gastric cancer. The objective of this application is to identify the underlying role of inflamma- tion as a trigger for the disruption of epithelial cell differentiation and thus the cascade leading to cancer. The central hypothesis of the current application is that Shh signaling drives gastric epithelial cell differentiation, function and the gastric immune response. Our hypothesis has been formulated on the basis of preliminary and published studies produced in the applicant's laboratory showing that deletion of Shh results in loss of normal glandular differentiation and function, suggesting that Shh is likely to be involved in the maintenance of adult gastric tissue homeostasis. In addition, Shh signaling is required for the development of H. pylori- induced gastritis. The rationale that underlies the research proposed is that, identified Hedgehog signaling tar- gets that are crucial for the development of gastritis and metaplasia may be applied as biomarkers for cancer diagnostics, prognostics and targeted therapeutics. Guided by strong preliminary data, this hypothesis is tested by pursuing two specific aims: 1) How does Hedgehog signaling regulate gastric epithelial cell differentiation in the adult stomach? And, 2) what is the role of Hedgehog signaling in the development of H. pylori-induced gastritis? The hypothesis will be tested using novel mouse models expressing constitutive and inducible pa- rietal cell-specific deletion of Shh and Shh deletion in the whole animal, adoptive splenocyte transfer, H. pylori- infected mouse models, and gastric and T cell cultures. The research proposed is innovative, because it fo- cuses on a novel approach that will allow us to assay changes in gastric epithelial cell differentiation and func- tion in relation to the loss and gain of Shh expression, independent of inflammation. This proposed research is significant because it is expected to provide knowledge required to potentially diagnose and effectively prevent gastric cancer in the pre-neoplastic stage.

描述（由申请人提供）：在胃发炎发展为胃癌的过程中，壁细胞不能分泌酸，并被化生粘液分泌细胞取代，这一过程称为胃萎缩。令人信服的证据表明，炎症，通常是由幽门螺杆菌（H。pylori），先于萎缩。虽然萎缩本身是胃癌前病变的可靠指标，但这种癌前病变发展的发病机制在很大程度上尚不清楚。壁细胞分泌许多调节胃上皮生长和分化的因子。将炎症和进展与萎缩联系起来的一个有利解释是由于这些因子的丢失。Sonic Hedgehog（Shh）信号通路是胃中表达的主要形态发生蛋白之一，但Shh调控胃上皮细胞分化的机制尚不清楚。Shh也是已知的细胞因子和趋化因子产生的调节因子，但其在H。尚未对幽门引起的胃炎进行研究。我们的长期目标是了解胃癌的发病机制。本申请的目的是鉴定炎症作为上皮细胞分化破坏的触发剂的潜在作用，从而导致癌症的级联反应。当前申请的中心假设是Shh信号传导驱动胃上皮细胞分化、功能和胃免疫反应。我们的假设是基于在申请人的实验室中产生的初步和公开的研究而制定的，这些研究表明Shh的缺失导致正常腺体分化和功能的丧失，这表明Shh可能参与维持成人胃组织稳态。此外，Shh信号传导是H.幽门螺杆菌引起的胃炎。所提出的研究的基本原理是，鉴定出的对胃炎和化生的发展至关重要的Hedgehog信号转导靶点可用作癌症诊断、肿瘤学和靶向治疗的生物标志物。在强有力的初步数据的指导下，通过追求两个具体目标来测试这一假设：1）刺猬信号传导如何调节成年胃中的胃上皮细胞分化？Hedgehog信号在H.幽门引起的胃炎将使用表达组成型和诱导型外周细胞特异性Shh缺失的新型小鼠模型和整个动物中的Shh缺失、过继性脾细胞转移、H.幽门螺杆菌感染的小鼠模型以及胃细胞和T细胞培养物。这项研究具有创新性，因为它侧重于一种新的方法，使我们能够分析胃上皮细胞分化和功能的变化与Shh表达的丧失和获得的关系，而与炎症无关。这项拟议的研究是重要的，因为它有望提供潜在诊断和有效预防胃癌前阶段所需的知识。