Immunometabolic and epigenetic effects of obesity on innate immune surveillance in cancer

肥胖对癌症先天免疫监视的免疫代谢和表观遗传影响

• 批准号: 10219918
• 负责人: Lydia Lynch
• 金额: $ 40.7万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219918
• 关键词: Accounting; Adult; Affect; Area; Awareness; Cardiovascular Diseases; Cell Count; Cell physiology; Cells; Complex; Data; Defect; Development; Disease; Economic Burden; Epidemic; Epigenetic Process; Healthcare Systems; Human; Immune; Immune System Diseases; Immune system; Immunologic Surveillance; Impairment; In Vitro; Infection; Innate Immune System; Lead; Malignant Neoplasms; Metabolic; Metabolic Pathway; Modification; Natural Killer Cells; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Overweight; Pathway interactions; Population; Prevalence; Preventable cancer cause; Prevention strategy; Proteins; RNA; Risk Factors; Sirolimus; Smoking; Surveys; cancer cell; cancer risk; cell injury; cytotoxicity; design; diet-induced obesity; frontier; functional restoration; health economics; in vivo; infection risk; insight; interdisciplinary approach; mouse model; neoplastic cell; obese patients; obese person; prevent; tumor; tumor progression

Project Summary Obesity has reached epidemic proportions globally with the biggest heath and economic burden being the many obesity-related diseases. Among these diseases, obesity is a strong risk factor for cancer, accounting for up to 49% of certain cancers. It is expected that obesity will soon replace smoking as the leading preventable cause of cancer. Despite increased public awareness and prevention strategies, the prevalence of obesity and related diseases continue. Therefore there is increased urgency to understand the pathways whereby obesity leads to other diseases, and to develop new strategies prevent their progression. It is now appreciated that obesity is associated with immune dysregulation, which may be the cause of some obesity related diseases. Natural killer (NK) cells are so-called due to their natural cytotoxicity against tumors cells. We have previously shown that obese individuals have reduced NK cell numbers and the remaining NK cells are unable to kill tumors cells efficiently. The key unanswered questions are 1) how does obesity induce NK cell defects, 2) Does NK cell impairment increase the risk of cancer in obesity, and 3) Can obesity induced immune dysfunction be reversed or prevented. This project will use a multi-disciplinary approach to decipher if epigenetic and metabolic changes in NK cells in obesity lead to their inability to survey and kill tumors. Immunometabolism is rapidly becoming an area of huge potential for treating disease, however much is still to be discovered. Results from this project will yield new insight into the complex changes that occur in innate immune cells in obesity and how they affect immune surveillance. It will also reveal a largely unexplored intersection between metabolic pathways and epigenetic modifications in the immune system. Our preliminary data shows that the effect of obesity is analogous to rapamycin treatment in terms of the effect on dampening NK cell functions. This likely impacts the ability of the innate immune system to act upon foreign or damaged cells when they encounter them, and may at least partly explain the increased risk of infection and cancer in obese individuals.

项目摘要 肥胖症已经在全球范围内达到了流行的程度，并带来了最大的健康和经济负担 是许多与肥胖相关的疾病。在这些疾病中，肥胖是一个强烈的风险因素 癌症，占某些癌症的49%。预计肥胖症将很快取代 吸烟是癌症的主要可预防原因。尽管公众意识增强了， 预防战略、肥胖症和相关疾病的流行仍在继续。因此，有 更迫切地需要了解肥胖导致其他疾病的途径，并 制定新的战略，防止他们的进步。 现在人们认识到，肥胖与免疫失调有关，这可能是原因 一些与肥胖相关的疾病。自然杀伤(NK)细胞之所以被称为自然杀伤细胞，是因为它们具有天然的 对肿瘤细胞的细胞毒作用。我们之前已经表明，肥胖的人NK细胞减少 细胞数量和剩余的NK细胞不能有效地杀死肿瘤细胞。钥匙 尚未回答的问题是1)肥胖是如何导致NK细胞缺陷的，2)NK细胞损伤 肥胖会增加患癌症的风险，3)肥胖引起的免疫功能障碍能否逆转或 被阻止了。这个项目将使用多学科方法来破译表观遗传和新陈代谢 肥胖患者NK细胞的变化导致它们无法检测和杀死肿瘤。 免疫新陈代谢正在迅速成为一个治疗疾病的巨大潜力领域，无论有多大 仍有待发现。这个项目的结果将使人们对复杂的变化有新的见解 肥胖患者的先天免疫细胞以及它们如何影响免疫监视。它还将揭示一个 代谢途径和表观遗传修饰之间的交集在很大程度上是未被探索的 免疫系统。我们的初步数据显示，肥胖的影响类似于雷帕霉素。 治疗对抑制NK细胞功能的影响。这可能会影响到 先天免疫系统在外来细胞或受损细胞遇到它们时对它们起作用，并可能在 这至少部分解释了肥胖者感染和癌症风险增加的原因。