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Porphyromonas gingivalis and Pancreatic Carcinogenesis in Mouse Models

小鼠模型中牙龈卟啉单胞菌与胰腺癌发生

基本信息

批准号：
9519194
负责人：
Caroline A Genco
金额：
$ 8.18万
依托单位：
TUFTS UNIVERSITY BOSTON
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：
2018-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9519194
关键词：
Address Animal Model Antibodies Atherosclerosis Biological Biological Models Caerulein Cancer Etiology Carcinoma Cardiovascular Diseases Cell Maturation Cessation of life Characteristics Chronic Collaborations Complex Data Dendritic Cells Detection Development Diabetes Mellitus Diagnosis Disease Disease Progression Dysplasia Effectiveness Epithelial Cells Etiology European Future Human Human Genetics Immune Immune response Immune system Immunization Immunology Immunosuppressive Agents Individual Infection Inflammation Inflammatory Intervention Knowledge Laboratories Lead Lesion Light Link Lipid A Lipoprotein Binding Malignant Neoplasms Malignant neoplasm of pancreas Mediating Membrane Modeling Modification Molecular Mus Mutant Strains Mice Organ Organism Pancreas Pancreatic Ductal Carcinoma Pancreatic Intraepithelial Neoplasia Pancreatitis Pathway interactions Patients Periodontal Diseases Porphyromonas gingivalis Premalignant Premature Birth Prevention Reporting Risk Role Signal Transduction Systemic disease T cell response TLR2 gene TLR4 gene Testing Universities Utah base cancer diagnosis cancer initiation cancer risk carcinogenesis cohort design epidemiologic data epidemiology study experience high risk human population study immunoregulation innovation insight mouse model mutant mouse model novel oral infection oral microbiome oral pathogen outcome forecast pathogen prevent prospective response vascular inflammation

项目摘要

Project Summary In the US, pancreatic cancer is the fourth leading cause of cancer-related death and is responsible for over 40,500 annual deaths. Prognosis is poor because most pancreatic cancers are diagnosed late in the progression of the disease, with only 6% of patients alive 5 years after initial diagnosis. Understanding the etiology of pancreatic cancer is critical to implement steps towards prevention and may provide insights on how to detect this highly fatal disease. Several epidemiological studies to date support an association between periodontal disease and pancreatic cancer risk. A recent epidemiological study of a large European cohort, documented a prospective two-fold increase in risk of pancreatic cancer among individuals with elevated antibodies to the periodontal pathogen, Porphyromonas gingivalis. The presence of P. gingivalis in the human oral microbiome was also recently associated with a higher risk of pancreatic cancer, suggesting an etiological role for P. gingivalis in pancreatic cancer. We have established that P. gingivalis promotes low-grade chronic inflammation through distinct immunomodulatory mechanisms. We hypothesize that P. gingivalis oral infection in Kras mutant mice will accelerate pancreatic cancer as a result of the unique ability of this pathogen to function in immune modulation. In this proposal, we will establish a model of P. gingivalis-accelerated pancreatic cancer in Kras mutant mice (Aim 1). We will also use the Kras mutant mouse model to examine the ability of P. gingivalis to accelerate pancreatic cancer development induced by prior or subsequent caerulein- induced pancreatitis (Aim 2). This R03 is led by Dr. Caroline Genco at Tufts University. Dr. Genco is a leader in the field of P. gingivalis and chronic inflammation. Her laboratory has defined the role of innate immune pathways that contribute to P. gingivalis-induced inflammation and the role of immunomodulation in pathogen-induced low-grade chronic inflammation. Dr. Murtaugh at University of Utah (Human Genetics) will provide expertise in pancreatic cancer mouse models. Leveraging our combined experience, we are uniquely poised to carry out the aims designed to establish a model of P. gingivalis-induced pancreatic cancer. The proposed studies will provide proof of concept results and preliminary mechanistic insight into PanIIN initiation and progression and are highly likely to lead to in-depth mechanistic studies into the cause, treatment, and prevention of pancreatic cancer. Knowledge gained from the current proposal will guide the design of new targets for detection, treatment, and prevention in humans of this extraordinarily lethal cancer.

项目总结