Project 1: Adipose tissue inflammation in obesity-promoted pancreatic cancer

项目1：肥胖促进的胰腺癌中的脂肪组织炎症

• 批准号: 10605225
• 负责人: Guido Erwin Michael Eibl
• 金额: $ 23.81万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605225
• 关键词: Acceleration; Adipocytes; Adipose tissue; Animal Model; Anti-Inflammatory Agents; Attenuated; CCL2 gene; Cells; Chemoprevention; Chronic Disease; Complex; Development; Diabetes Mellitus; Diet; Dietary Component; Disease; Dose; Economics; Excision; FDA approved; Genetic; Growth; Growth and Development function; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Intervention; KRAS oncogenesis; KRASG12D; Kinetics; Lesion; Life; Link; Lipids; Macrophage; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolic Diseases; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Non-Malignant; Obesity; Obesity associated cancer; Organoids; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Positive Reinforcements; Primary Prevention; Production; Proliferating; Risk Factors; Role; Secondary Prevention; Signal Transduction; Societies; Sociology; TLR4 gene; Testing; Time; Tissues; Transcription Coactivator; Tumor Promotion; Visceral; cancer prevention; cytokine; design; diet-induced obesity; drug repurposing; efficacious intervention; gastrointestinal; high risk; lipophilicity; mouse model; novel; novel strategies; obese patients; obesity genetics; obesogenic; pancreas development; pancreatic cancer model; pancreatic ductal adenocarcinoma cell; prevent; programs; rho; translational approach; translational impact; tumor

PROJECT SUMMARY There is substantial evidence that obesity is a risk factor for the development of several chronic diseases, including pancreatic ductal adenocarcinoma (PDAC). These diseases pose an incredible economic and sociologic burden to society. Although the underlying mechanisms are likely multi-faceted, inflammation certainly plays an important role in the link between obesity and cancer. Infiltrating inflammatory cells as well as systemic and local levels of pro-inflammatory mediators provide in ideal micro-milieu for tumor development and growth. Anti-inflammatory strategies have been shown in many animal models to delay or prevent the development of cancers and are widely considered intriguing approaches for cancer prevention. In addition, obesity-associated adipose tissue inflammation, in particular visceral adipose tissue inflammation, correlates strongly to the development of metabolic diseases, e.g. type 2 diabetes mellitus, and (gastrointestinal) cancer. In previous studies an obesogenic diet was found to significantly accelerate the development and progression of PDAC precursor lesions (pancreatic intraepithelial neoplasia: PanIN), and to increase the incidence of invasive and metastatic PDAC in the conditional KrasG12D (KC) mouse model. This was associated with a substantial inflammation of the pancreas and visceral adipose tissue (VAT). The overarching hypothesis of this Project is that obesity leads to VAT inflammation, which is a critical (promotional) driver of PDAC development and growth. Targeting obesity-associated VAT inflammation with FDA-approved, repurposed drugs may represent an intriguing and novel strategy to prevent PDAC development and progression. In Specific Aim 1 the kinetics of obesity-induced AT inflammation and PDAC development will be investigated. The effects of diet-induced obesity will be compared with genetically-induced obesity. To identify efficacious interventional and translational strategies the dose- and time-dependent effects of statins on AT inflammation and PDAC development will be evaluated in Specific Aim 2. The molecular mechanisms underlying the effects of statins on AT inflammation and the effects of AT inflammation on PanIN/organoid growth ex vivo will be determined in Specific Aim 3 with a focus on YAP/TAZ, transcriptional co-activators in the Hippo pathway. The studies will provide evidence of a critical role of obesity-induced VAT inflammation in PDAC growth and will identify novel mechanistic pathways and targets. Since statins are widely used and FDA-approved drugs the successful completion of the studies will have an immediate and translational impact on patients with PDAC. Generally, the results may also be transferable to other obesity-related cancers and even non-malignant chronic diseases.

项目摘要 有大量证据表明肥胖是发展几种慢性疾病的危险因素， 包括胰腺导管腺癌（PDAC）。这些疾病构成了令人难以置信的经济和 社会的社会学负担。尽管基本机制可能是多方面的，但炎症 当然，在肥胖与癌症之间的联系中起着重要作用。浸润炎症细胞为 以及促炎性介体的系统性和局部水平为肿瘤提供理想的微米岛 发展与成长。在许多动物模型中已经显示了抗炎策略以延迟或 防止癌症的发展，并被广泛认为是预防癌症的有趣方法。在 另外，肥胖相关脂肪组织炎症，特别是内脏脂肪组织炎症， 与代谢疾病的发展密切相关，例如2型糖尿病和（胃肠道） 癌症。在先前的研究中，发现肥胖饮食可显着加速发展和 PDAC前体病变的进展（胰腺内肿瘤：Panin），并增加 有条件的KRASG12D（KC）小鼠模型中侵入性和转移PDAC的发生率。这是相关的 胰腺和内脏脂肪组织（VAT）严重炎症。总体假设 这个项目的是肥胖会导致增值税炎症，这是PDAC的关键（促销）驱动力 发展与成长。用FDA批准的，重新利用的药物靶向肥胖相关的增值税炎症 可能代表了防止PDAC发展和进展的有趣而新颖的策略。在特定目标中 1将研究炎症和PDAC发育时肥胖引起的动力学。效果 饮食引起的肥胖症将与遗传引起的肥胖症进行比较。确定有效的介入和 翻译策略汀类药物对炎症和PDAC的剂量和时间依赖性作用 开发将在特定的目标2中评估。汀类药物作用的分子机制 在炎症和炎症对panin/Organoled的影响的影响将在体内确定 特定的目标3，重点是河马途径中的YAP/TAZ，转录共激活因子。研究会 提供肥胖引起的增值税炎症在PDAC生长中的关键作用的证据，并将识别新颖 机械途径和目标。由于他汀类药物被广泛使用并获得FDA批准的药物成功 研究的完成将对PDAC患者产生直接和翻译的影响。通常， 结果也可以转移到其他与肥胖相关的癌症甚至非恶性慢性疾病中。