Dysregulation of Inflammasome in Pathogen/Carcinogen Induced Diseases

Accumulating data show that inflammasome activation is associated with many diseases, including chronic renal and plumorary diseases and malignant disorders. Although the etiologies of many diseases have been identified, the molecular link between these pathogen / carcinogen leading to disease are still obscure. Inflammasome may play a crucial and common role which response to chronic inflammation leading to disease development. In the program study, we propose to investigate four pathogen/carcinogen induced chronic diseases which may be resulted from dysregulation of inflammasome: areca nut induced oral cancer, Helicobacter pylori associated gastric cancer, microbiota caused chronic obstructive pulmonary disease, and Bion/nanobacteria induced chronic renal disease. Improving our understanding of inflammasome signaling pathways could provide insight into the pathogenesis of diseases, and serve as knowledge foundation for further development of therapeutic or diagnostic modality for clinical applications. Each sub-project is briefly described below. Project 1: Functional investigation of inflammasome in areca nut induced oral cancer. In Taiwan, the incidence of oral cancer has become the 5th leading cancer, the 4th leading cancer in male since 2009. Areca nut chewing is the most common habit in oral cancer patients, suggesting close link of this habit with oral carcinogenesis. Chronic inflammation is commonly found in oral cancer patients with areca nut chewing, yet the precise mechanisms between these associations are largely unknown. To this regard, in the present study, we will explore inflammasome associated molecules and pathway network in oral keratinocytes and cancer cells in response to areca nut treatment. The biological functions of specific inflammasome molecules in associated with malignant transformation will be investigated by over- or silencing expression in oral cancer cell lines, as well as in specific inflamasome knockout mice. The clinical association study will be conducted to determine whether dysregulation of inflammasome molecules is correlated with areca nut chewing habit in oral cancer patients. Understanding of inflammasome associated pathways should provide valuable information on the carcinogenesis of areca nut-induced oral cancer. Project 2: The role of deregulated inflammation associated proteins in gastric cancer. Chronic infection of the gastric mucosa with Helicobacter pylori has long been recognized as a significant risk factor for gastric cancer. Infection inducing chronic inflammation associate proteins expression plays an important role in tumorigenesis. In this study, we will determine the role of deregulated inflammation associated proteins during gastric carcinogenesis. A group of inflammation associated candidate proteins such as macrophage migration inhibitory factor (MIF), neutrophil defensin 1(NDE), neutrophil gelatinase-associated lipocalin (NGAL), Interleukin (IL)-32 and interferon-induced transmembrane (IFITM) highly expressing in gastric cancer tissue will be further studied and investigated their clinicopathological significance. Furthermore, the function or regulation of the candidate proteins will be studied in vivo inflammasome-related knockout mice. Elucidation of the molecular and cellular pathways that relate inflammation with cancer may provide additional opportunities to develop complementary therapies that target the inflammatory microenvironment of the cancer. Project 3: Role of inflammasome and microbiota in Chronic Obstructive Pulmonary Disease. Chronic obstructive pulmonary disease (COPD) which is expected to reach the third mortality rate in worldwide diseases in the year 2020 is a fatal lung disease characterized by progressive and irreversible airflow limitation. The inflammasome activation and other inflammations-based mechanisms in COPD remain not totally determined. In this proposal, using animal study models, we aim to investigate and correlate the relationship between imbalance of host innate immune inflammation and COPD. Results from this study will be translated to clinical prevention and treatment of COPD. The COPD inflammatory mechanisms will be used as important messages for development of COPD prevention strategy. Modulation of intestinal microbiota structure will be used as an important way of COPD prevention and treatment. Project 4: Bion induced inflammasome activation in chronic renal disease. Bion/nanobacteria is a family of nano-sized mineralo-organic complexes, which are physiological remnants of normal calcium homeostasis. Bion/nanobacteria have in fact been documented in all the body fluids that we have studied to date, including serum and a number of other body fluids such as saliva, urine, cerebrospinal fluid, ascites fluid, synovial joint fluid, pleural effusion. However, the property of bion is not well characterized. Serial studies are designed to investigate the entity of bion and to evaluate the pathogenesis of bion, including cytotoxicity assay, inflammasome activation, proteomic study, metabolomic study, immunohistochemistry, function characterization using cellular and animal models, as well as clinical association study.

Project ID:PC10301-0844
External Project ID:NSC101-2632-B182-001-MY3