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，胰腺癌是癌症相关死亡的第四大原因，占 每年有40,500人死亡。预后很差，因为大多数胰腺癌都是在晚期诊断出来的。 疾病的进展，只有6%的患者在最初诊断后5年内存活。了解 胰腺癌的病因学是实施预防措施的关键，并可能提供关于如何 来检测这种高度致命的疾病。到目前为止的几项流行病学研究支持 牙周病和胰腺癌的风险。最近一项针对一大批欧洲人群的流行病学研究， 记录表明，在患有胰腺癌的患者中，患胰腺癌的风险预期增加两倍 牙周病原体牙龈卟啉单胞菌的抗体。牙龈假单胞菌在人类体内的存在 最近，口腔微生物组也与胰腺癌的高风险有关，这表明了一种病因 牙龈假单胞菌在胰腺癌中的作用。我们已经确定牙龈假单胞菌促进低度慢性牙周炎 炎症通过不同的免疫调节机制。我们推测牙龈假单胞菌口腔感染 在Kras中，突变小鼠将加速胰腺癌，因为这种病原体具有独特的能力 在免疫调节中的作用。在本方案中，我们将建立一种牙龈假单胞菌加速感染的模型。 Kras突变小鼠的胰腺癌(目标1)。我们还将使用Kras突变小鼠模型来检查 能力的提高。 牙周炎会加速 先前或随后的雨蛙素诱导的胰腺癌进展- 诱导性胰腺炎(AIM 2)。 这个R03是由塔夫茨大学的Caroline Genco博士领导的。Genco博士是牙龈假单胞菌领域的领导者， 慢性炎症。她的实验室已经确定了先天免疫途径在P。 牙周炎及免疫调节在病原菌诱导的低度慢性牙周炎中的作用 发炎。犹他大学(人类遗传学)的Murtaugh博士将提供胰腺癌方面的专业知识 老鼠模型。利用我们的联合经验，我们将以独特的姿态实现旨在 建立牙龈假单胞菌诱导的胰腺癌模型。拟议的研究将提供以下证据 概念结果和对PanIin启动和进展的初步机制洞察，很有可能 引导对胰腺癌的病因、治疗和预防进行深入的机制研究。 从当前提案中获得的知识将指导设计新的检测、治疗和治疗目标 在人类中预防这种极其致命的癌症。