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

• 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
• 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

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.

项目摘要 在美国，胰腺癌是与癌症相关死亡的第四个主要原因，并负责过度 每年40,500人死亡。预后很差，因为大多数胰腺癌在后期被诊断出 该疾病的进展，最初诊断后5年仅活着6％的患者。了解 胰腺癌的病因对于实施预防步骤至关重要 检测这种高度致命的疾病。迄今为止的一些流行病学研究支持 牙周疾病和胰腺癌风险。最近对大型欧洲队列的流行病学研究， 记录了有升高的人的胰腺癌风险的前瞻性增加 牙周病原体卟啉单胞菌的抗体。人类中牙龈疟原虫的存在 口服微生物组最近也与胰腺癌的风险更高有关，这表明病因 牙龈疟原虫在胰腺癌中的作用。我们已经确定牙龈疟原虫促进了低级慢性 通过不同的免疫调节机制发炎。我们假设牙龈疟原虫口腔感染 在Kras突变体中，小鼠将由于这种病原体的独特能力而加速胰腺癌 免疫调节功能。在此提案中，我们将建立牙龈疟原虫加速的模型 KRAS突变小鼠中的胰腺癌（AIM 1）。我们还将使用KRAS突变小鼠模型检查 P.的能力 牙龈加速 胰腺癌发育是由先前或随后的钙蛋白酶诱导的 诱导胰腺炎（AIM 2）。 该R03由塔夫茨大学的Caroline Genco博士领导。 Genco博士是牙龈疟原虫和 慢性炎症。她的实验室定义了有助于P的先天免疫途径的作用。 牙龈毒素引起的炎症和免疫调节在病原体诱导的低度慢性中的作用 炎。犹他大学的Murtaugh博士（人类遗传学）将提供胰腺癌的专业知识 鼠标模型。利用我们的综合经验，我们完全准备实现旨在的目标 建立牙龈疟原虫诱导的胰腺癌的模型。拟议的研究将提供证明 概念结果和对Paniin启动和进展的初步机理洞察力，很可能 导致对胰腺癌的原因，治疗和预防的深入机理研究。 从当前提案中获得的知识将指导设计新目标以进行检测，治疗和 人类预防这种致命的癌症。