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: 8039853
• 负责人: Yana Zavros
• 金额: $ 37.93万
• 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/8039853
• 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; 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. PUBLIC HEALTH RELEVANCE: The proposed research has relevance to public health because gastric cancer continues to be the second leading cause of cancer-related death worldwide. The successful completion of this proposal will have a positive impact on our current knowledge of gastric biology, especially the aspects that are important in understanding the pathogenesis of gastric cancer. In addition, identifying the role of Hedgehog signaling in the development of neoplasia will allow for the therapeutic intervention to target the treatment or prevention of gastric cancer.

描述（由申请人提供）：在胃炎发展为胃癌的过程中，胃壁细胞不能分泌酸，取而代之的是化生的分泌粘液的细胞，这一过程称为胃萎缩。令人信服的证据表明，通常由幽门螺杆菌（h.p ylori）引起的炎症先于萎缩。虽然萎缩本身是胃肿瘤前病变的可靠指标，但这种癌前病变的发病机制在很大程度上是未知的。胃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种受欢迎的解释是由于这些因素的丧失。Sonic Hedgehog （Shh）信号通路是胃中表达的主要形态因子之一，但其调控胃上皮细胞分化的机制尚不清楚。Shh也是一种已知的细胞因子和趋化因子产生的调节因子，但其在幽门螺杆菌诱导的胃炎发展中的作用尚未被研究。我们的长期目标是了解胃癌的发病机制。本应用的目的是确定炎症作为上皮细胞分化破坏的触发因素的潜在作用，从而导致癌症的级联反应。目前应用的中心假设是Shh信号驱动胃上皮细胞分化、功能和胃免疫反应。我们的假设是基于申请人实验室的初步和已发表的研究，这些研究表明，Shh的缺失会导致正常腺体分化和功能的丧失，这表明Shh可能参与成人胃组织稳态的维持。此外，Shh信号在幽门螺杆菌诱发的胃炎的发展中是必需的。这项研究提出的基本原理是，已确定的对胃炎和化生的发展至关重要的Hedgehog信号靶标可能被用作癌症诊断、预后和靶向治疗的生物标志物。在强有力的初步数据的指导下，这一假设通过追求两个特定目标来验证：1)Hedgehog信号如何调节成人胃上皮细胞的分化？2) Hedgehog信号在幽门螺杆菌性胃炎发生发展中的作用是什么？这一假设将通过新的小鼠模型进行验证，这些小鼠模型表达了构成性和可诱导性的生殖细胞特异性Shh缺失和整个动物的Shh缺失，过继性脾细胞转移，幽门螺杆菌感染小鼠模型，以及胃和T细胞培养。这项研究具有创新性，因为它提出了一种新的方法，使我们能够检测与Shh表达的丧失和获得相关的胃上皮细胞分化和功能的变化，而不受炎症的影响。本研究具有重要意义，因为它有望提供潜在诊断和有效预防胃癌肿瘤前期所需的知识。