Interaction between Chronic Stress and Obesity in Pancreatic Cancer Progression

慢性压力和肥胖在胰腺癌进展中的相互作用

基本信息

批准号：
10409304
负责人：
Guido Erwin Michael Eibl
金额：
$ 21.88万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10409304
关键词：
Adrenergic Agents Amygdaloid structure Applications Grants Calories Cancer Etiology Cardiovascular Diseases Catecholamines Cell Proliferation Cessation of life Chemoprevention Chemopreventive Agent Chronic Chronic stress Clinical Complex Development Diet Disease Progression Environmental Risk Factor Event FDA approved Fatty acid glycerol esters Functional disorder Genes Genetic Models Growth Hematologic Neoplasms High Fat Diet High Prevalence Hormones Human Insulin Receptor Insulin Resistance KRAS2 gene KRASG12D Knowledge Lead Lesion Link Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of pancreas Mediating Metabolic Metabolic syndrome Molecular Mus Mutate Mutation Neurobiology Neurons Neurotransmitters Non-Insulin-Dependent Diabetes Mellitus Obesity Oncogenes Outcome Outcome Study Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pathway interactions Pharmaceutical Preparations Prevention Receptor Signaling Research Risk Signal Pathway Signal Transduction Social isolation Solid Solid Neoplasm Stimulant Stress Survival Rate System Western World Work beta-adrenergic receptor diet-induced obesity dietary control epidemiology study experimental study human disease islet stem cells mouse model neuropeptide Y novel novel strategies pancreas development pancreatic cancer cells pancreatic cancer model pancreatic cell line pancreatic ductal adenocarcinoma cell pre-clinical preclinical study prevent response stressor synergism therapeutic development tumor tumor progression virtual

项目摘要

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human diseases, with overall 5-year survival rate of only 9%. PDAC is estimated to become the 2nd leading cause of cancer-related deaths in the US within the next decade. Virtually all PDACs involve activating mutations in the KRAS oncogene, which are thought to represent an initiating event. Although mutated Kras is necessary for PDAC initiation it is not sufficient for the rapid progression of the disease. In addition to mutation in tumor suppressive genes that collaborate with mutated Kras, there is increasing recognition of the importance of environmental factors in PDAC progression. In this context, many epidemiological studies have linked obesity with increased risk for developing PDAC and other clinically aggressive cancers. Preclinical studies using the conditional KrasG12D mouse model (KC), demonstrated that KC mice subjected to high fat calorie diet became obese and displayed a marked increase in PanIN lesions and invasive PDAC. There is also evidence that chronic stress accelerates the progression of a variety of tumor types, including PDAC through β-adrenergic signaling. Recent studies identified a complex neurobiological interaction between chronic stress, diet-induced obesity (DIO) and insulin resistance. The objective of this proposal is to explore critical gaps in current knowledge concerning the interaction between stress and diet-induced obesity on PDAC progression. Specifically, we propose to examine the impact of different chronic stressors on the development of PDAC using a genetically modified mouse model that recapitulates key features of the human disease. Mechanistic studies in PDAC cells will elucidate the molecular mechanisms that mediate the growth-promoting effects of stress neurotransmitters, including crosstalk between β-adrenergic receptors and insulin receptor signaling pathways leading to PDAC cell proliferation. Our central hypothesis proposed is that interaction between chronic stress and diet-induced obesity potently accelerates the progression of Kras-initiated precursor lesions to invasive PDAC in KC mice. To explore this hypothesis and elucidate the molecular mechanism(s) involved, we propose two Specific Aims: 1) Determine the development of PanINs and PDAC using the conditional KrasG12D mouse model subjected to chronic stressors in combination with diet-induced obesity (DIO) and define the chemopreventive effects of β- adrenergic receptor blocking in each condition. 2) Determine the molecular pathways implicated in catecholamine-induced PDAC cell proliferation using human and mouse pancreatic cell lines and identify crosstalk mechanisms between β-adrenergic receptor and insulin receptor signaling systems. The identification that chronic stress interacting with DIO is a potent stimulant of PDAC progression as well as the elucidation of the signaling mechanisms that drive PDAC development in response to stress and DIO, as proposed in this application, will be of major translational significance to discover novel targets and drugs for PDAC prevention.

抽象的胰腺导管腺癌 (PDAC) 是人类最致命的疾病之一，总体 5 年发病率据估计，PDAC 的生存率仅为 9%，成为癌症相关死亡的第二大原因。美国在未来十年内几乎所有 PDAC 都涉及 KRAS 癌基因的激活突变，这些突变是尽管突变的 Kras 是 PDAC 启动所必需的，但实际上并非如此。除了肿瘤抑制基因的突变之外，这足以导致疾病的快速进展。与突变的 Kras 合作，人们越来越认识到环境因素在在这种情况下，许多流行病学研究已将肥胖与 PDAC 风险增加联系起来。使用条件 KrasG12D 开发 PDAC 和其他临床侵袭性癌症。小鼠模型（KC），证明接受高脂肪热量饮食的 KC 小鼠变得肥胖并表现出 PanIN 病变和侵袭性 PDAC 显着增加，也有证据表明慢性压力会加速。多种肿瘤类型的进展，包括通过 β-肾上腺素能信号传导的 PDAC。确定了慢性压力、饮食引起的肥胖 (DIO) 和胰岛素之间复杂的神经生物学相互作用该提案的目的是探讨当前关于抵抗的知识的关键差距。具体来说，我们建议压力和饮食引起的肥胖之间的相互作用。使用转基因方法检查不同慢性压力源对 PDAC 发展的影响概括人类疾病关键特征的小鼠模型将在 PDAC 细胞中进行机制研究。阐明介导应激神经递质促进生长作用的分子机制，包括导致 PDAC 的 β-肾上腺素能受体和胰岛素受体信号通路之间的串扰我们提出的中心假设是慢性压力和饮食诱导之间的相互作用。肥胖可有效加速 KC 小鼠中 Kras 引发的病变的进展，从而导致侵袭性 PDAC。为了探索这一假设并阐明所涉及的分子机制，我们提出了两个具体目标： 1) 使用条件 KrasG12D 小鼠模型确定 PanIN 和 PDAC 的发育慢性压力源与饮食引起的肥胖（DIO）相结合，并定义了β-的化学预防作用每种情况下肾上腺素能受体阻断 2) 确定涉及的分子途径。使用人和小鼠胰腺细胞系进行儿茶酚胺诱导的 PDAC 细胞增殖并鉴定 β-肾上腺素能受体和胰岛素受体信号系统之间的串扰机制。确定与 DIO 相互作用的慢性应激是 PDAC 进展的有效刺激物阐明驱动 PDAC 发育以响应压力和 DIO 的信号机制，如本申请中提出的，对于发现新的靶点和药物具有重大转化意义 PDAC 预防。