Determining the contribution of microbial-derived metabolites to protective immunity in obesity-driven cancer risk.

摘要：肥胖与13种癌症的风险增加有关。关键问题是如何以及要做什么 肥胖介导的慢性炎症增加的潜在机制可能会增加癌症风险 在“保护性免疫”失败的情况下。这一知识鸿沟代表着一个尚未开发的机会，我们的许多人- 纪律团队是唯一有资格进行探索的团队，其使命是提高对癌症风险的了解。我们有 先前发现肥胖会改变T细胞和巨噬细胞的功能，从而降低抗肿瘤保护作用 并拥有对这一跨学科挑战至关重要的人体研究方面的专业知识。我们的目标是找出 不同临床前模型中癌症风险介质在人类受试者中的关联性和测试机制 沿着一个“肥胖微生物代谢产物保护性免疫”的轴心。我们的假设是，肥胖改变了 肠道微生物通过调节失调的保护性免疫增加癌症风险。 目标1将定义肥胖介导的微生物衍生代谢产物的失调及其对免疫Phe的影响。 通过检查不同的受试者在癌症风险较高的人类受试者中的基因分型和保护性免疫 1a)不同年龄和肥胖程度的患者；以及1b)减肥手术前后的肥胖患者。捐赠者将被抽出 来自孟菲斯地区，那里的人口高度多样化，65%的非裔美国人具有很高的集中度- 肥胖症。患者分析将为补充临床前模型的研究提供信息，以允许机制- Nistic研究以确定癌前微环境中的保守机制。目标2将阻止- 通过检测自发性免疫细胞来挖掘微生物代谢产物对癌症风险的影响 乳腺癌转基因模型在对高脂肪的潜伏期和致肥性反应方面已建立的异质性 饮食、循环胆汁酸和肠道微生物。AIM 3将测试一种特定微生物的饮食给药 分离的代谢物或微生物对互补致癌和同基因小鼠模型保护性免疫的影响 分别是由肥胖引起的乳腺癌。人体和小鼠模型研究与前研究相辅相成 体内和体外研究将测试潜在的机制，以确定微生物修饰的代谢物如何 可能会影响免疫--癌细胞串扰。为跨财团活动预留合作资金用于 跨异种瘦身和肥胖人群和模型的风险评估旨在增加协同效应 通过NCI的代谢失调和癌症风险计划对我们的研究结果的影响。总而言之，结果将 定义有益的微生物衍生代谢物，影响保护性免疫，以减少癌症的发生。 因此，这一建议的战略在概念上是原创的，具有创新性，对界定保守的非政府组织具有重要意义。 抑制癌症风险的可笑机制。产生的研究结果将产生很大的影响，因为肥胖- 相关的病因对风险的影响将是不同的，这项研究旨在调查 不同的机制可以转化为更好的风险管理，以改善患者结局。

SUMMARY: Obesity is associated with increased risk for 13 cancers. Critical questions are how and to what extent underlying mechanisms of obesity-mediated increases in chronic inflammation may increase cancer risk in a failure of “protective immunity”. This knowledge gap represents an untapped opportunity that our multidis- ciplinary team is uniquely qualified to explore with a mission to improve understanding of cancer risk. We have previously shown obesity alters T cell and macrophage functions that could decrease anti-tumor protections and have expertise in human studies essential for this interdisciplinary challenge. Our objective is to identify associations in human subjects and test mechanisms of mediators of cancer risk in various pre-clinical models along an “obesitymicrobes metabolites protective immunity” axis. Our hypothesis is that obesity-altered gut microbes enhance cancer risk through dysregulated protective immunity that allows increased initiation. Aim 1 will define obesity-mediated dysregulation of microbial-derived metabolites and impacts on immune phe- notypes and protective immunity in human subjects at greater risk for cancer by examining diverse subjects 1a) of varied age and adiposity; and 1b) obese patients pre- and post- bariatric surgery. Donors will be drawn from the Memphis area, which offers a highly diverse population with 65% African Americans with a high inci- dence of obesity. Patient analyses will inform studies in complementary pre-clinical models to allow for mecha- nistic investigation to identify conserved mechanisms in the pre-cancer microenvironment. Aim 2 will deter- mine the impact of microbially-derived metabolites on cancer risk by examining immune cells in spontaneous transgenic models of breast cancer with established heterogeneity in latency, obesogenic response to high fat diet, circulating bile acids, and gut microbes. Aim 3 will test dietary administration of a specific microbially-de- rived metabolite or microbe on protective immunity in complementary carcinogenic and syngeneic models of obesity-mediated breast cancer, respectively. Human subject and murine model studies complemented by ex vivo and in vitro studies will test underlying mechanisms to determine how microbially-modified metabolites may impact immune-cancer cell crosstalk. Collaborative funds for cross-consortium activities are reserved for risk assessment across heterogenous lean and obese populations and models across aims to add synergistic impact to our findings through NCI’s Metabolic Dysregulation and Cancer Risk Program. In sum, outcomes will define beneficial microbially-derived metabolites that impact protective immunity to reduce cancer initiation. Thus, the strategy of this proposal is conceptually original, innovative, and significant to define conserved un- derlying mechanisms that suppress cancer risk. Findings generated will have high impact because the obesity- associated etiological impacts on risk will be heterogeneous and this study is designed to investigate those varied mechanisms to translate to better risk management to improve patient outcomes.