Immune Regulation of Gastric Cancer

胃癌的免疫调节

基本信息

批准号：
10709271
负责人：
Jonathan Busada
金额：
$ 23.78万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709271
关键词：
Acceleration Adrenal Glands Adrenalectomy Affect Anti-Inflammatory Agents Atrophic Gastritis Autoimmune Automobile Driving CD4 Positive T Lymphocytes Cancer Etiology Cancer Model Cancer Patient Cells Cessation of life Chronic Crohn&apos s disease Data Development Diagnosis Disease Dysplasia Environment Epithelium Future Gastric Adenocarcinoma Gastric Metaplasia Gastric mucosa Gastritis Glucocorticoid Receptor Glucocorticoids Goals Helicobacter Helicobacter Infections Helicobacter pylori Hormones Human Hyperactivity Immune Infection Inflammation Inflammatory Inflammatory Response Insulin Knowledge Laboratories Link Malignant Neoplasms Metaplasia Mus Pathogenicity Pathway interactions Phenotype Population Preneoplastic Conditions Production Publishing Regulation Resistance Role Sampling Severities Signal Pathway Signal Transduction Steroid-resistant asthma Stomach Stomach Neoplasms T-Cell Activation T-Lymphocyte Testing Time Tissues cancer risk carcinogenesis chronic inflammatory disease cytokine diagnostic tool efficacy evaluation gastric cancer prevention gastric carcinogenesis high throughput screening immunoregulation malignant stomach neoplasm mortality mouse model novel diagnostics novel therapeutic intervention polarized cell prevent recruit response spasmolytic polypeptide steroid hormone transcriptome tumor tumor microenvironment

项目摘要

ABSTRACT - Immune Regulation of Gastric Cancer Gastric cancer is the 4th leading cause of cancer deaths worldwide. Over 90% of gastric cancers are associated with long-term Helicobacter pylori infection. However, the infection alone has limited pathogenic effects on the gastric mucosa. Rather, the infection triggers massive gastric inflammation, which becomes increasingly hyper- active, damaging the stomach and creating the requisite environment for carcinogenesis. However, the mecha- nisms and pathways that regulate the onset of hyperactive inflammation are unknown. Glucocorticoids are potent anti-inflammatory steroid hormones produced by the adrenal glands. We have shown that glucocorticoids are critical for suppressing pathogenic gastric inflammation. Adrenalectomized mice spontaneously develop massive gastric inflammation driving a potentially pre-neoplastic condition called Spasmolytic polypeptide-expressing metaplasia (SPEM). Glucocorticoid signaling is also disrupted in gastric cancers, but the role of these hormones in gastric cancer development and progression has not been studied. The overall goal of this proposal is to establish the role of glucocorticoids in preventing Helicobacter-induced gastric cancer development. Our prelim- inary data suggest that endogenous glucocorticoids are critical regulators of the gastric inflammatory response to Helicobacter infection. Loss of glucocorticoid signaling accelerates gastric epithelial damage, metaplasia, and dysplasia. Thus, the loss of glucocorticoid signaling likely accelerates Helicobacter-induced gastric cancer de- velopment. However, glucocorticoid protection from gastric cancer development has never been studied. Spe- cific Aim 1 will examine how glucocorticoid signaling regulates gastric T cell activation and polarization. Specific Aim 2 will examine how long-term Helicobacter infection disrupts endogenous glucocorticoid signaling within the stomach, promoting hyperactive inflammation even upon Helicobacter eradication. Specific Aim 3 will utilize the INS-GAS mouse model of gastric carcinogenesis to study whether glucocorticoid signaling protects from gastric cancer development. Moreover, we will use fresh tumor samples to examine how glucocorticoid signaling mod- ulates the tumor microenvironment in humans. These studies will be the first to investigate how glucocorticoid signaling regulates gastric cancer development. Ultimately, the knowledge generated here will facilitate the launch of human studies and the development of novel diagnostic and therapeutic strategies to prevent gastric cancer.

摘要 - 胃癌的免疫调节胃癌是全球第四大癌症死亡原因。 90%以上的胃癌与长期感染幽门螺杆菌。然而，单独感染对细菌的致病作用有限。胃粘膜。相反，感染会引发严重的胃炎症，这种炎症会变得越来越严重。活跃，损害胃，为致癌创造必要的环境。然而，机甲—— 调节过度炎症发作的机制和途径尚不清楚。糖皮质激素是有效的肾上腺产生的抗炎类固醇激素。我们已经证明糖皮质激素是对于抑制致病性胃炎症至关重要。肾上腺切除的小鼠自发发育成巨大的胃部炎症导致一种潜在的肿瘤前期病症，称为解痉多肽表达化生（SPEM）。糖皮质激素信号在胃癌中也会受到干扰，但这些激素的作用尚未研究其在胃癌发生和进展中的作用。该提案的总体目标是确定糖皮质激素在预防螺杆菌诱导的胃癌发展中的作用。我们的预演—— 初步数据表明内源性糖皮质激素是胃炎症反应的关键调节剂到螺杆菌感染。糖皮质激素信号传导的丧失会加速胃上皮损伤、化生和发育不良。因此，糖皮质激素信号传导的丧失可能会加速螺杆菌诱导的胃癌的进展。发展。然而，从未研究过糖皮质激素对胃癌发展的保护作用。斯佩- 具体目标 1 将研究糖皮质激素信号如何调节胃 T 细胞激活和极化。具体的目标 2 将研究长期螺杆菌感染如何破坏体内内源性糖皮质激素信号传导即使根除螺杆菌，也会促进胃部过度活跃的炎症。具体目标 3 将利用 INS-GAS 胃癌小鼠模型研究糖皮质激素信号是否能预防胃癌癌症的发展。此外，我们将使用新鲜的肿瘤样本来检查糖皮质激素信号如何调节模拟人类肿瘤微环境。这些研究将首次探讨糖皮质激素如何信号传导调节胃癌的发展。最终，这里产生的知识将促进开展人体研究并开发新的诊断和治疗策略来预防胃病癌症。