TLR4 in obesity-driven liver cancer

TLR4 在肥胖驱动的肝癌中的作用

• 批准号: 8737016
• 负责人: Jorge Matias Caviglia
• 金额: $ 13.04万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737016
• 关键词: Ablation; Adipose tissue; Advisory Committees; Affect; Albumins; Animal Model; Apoptosis; Area; Bacteria; Bacterial Translocation; Basic Science; Biomedical Research; Blood Circulation; Cancer Etiology; Cause of Death; Cell Proliferation; Cells; Cessation of life; Cholesterol; Chronic; Communities; Data; Development; Diagnosis; Diet; Fatty Liver; Fatty acid glycerol esters; Fructose; Funding; Future; Gene Expression; Genetic; Goals; Grant; HMGB1 Protein; Health; Hepatic; Hepatic Stellate Cell; Hepatocarcinogenesis; Hepatocyte; Hispanics; Human; Incidence; Inflammatory; Injury; Institution; Interleukin-6; Investigation; Journals; Knock-out; Knockout Mice; Kupffer Cells; Ligands; Lipopolysaccharides; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Mentors; Metabolic syndrome; Minority; Modeling; Mus; Mutation; Myelogenous; Myeloid Cells; Obesity; Pathway interactions; Patients; Physicians; Plasma; Population; Prevention; Primary carcinoma of the liver cells; Principal Investigator; Publications; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Saturated Fatty Acids; Scientist; Signal Pathway; Signal Transduction; Sterilization; TNF gene; Technology; Testing; Time; Training; Transgenic Mice; Universities; Writing; anticancer research; base; cancer risk; cancer therapy; career; career development; cell type; cytokine; falls; fast food; genotoxicity; gut microbiota; lipopolysaccharide-binding protein; liver inflammation; liver injury; macrophage; meetings; novel; prevent; programs; receptor; response; skills; toll-like receptor 4; tumor microenvironment; tumorigenic

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Liver cancer in Hispanics and Blacks is 2 to 4 times more frequent than in Whites. Obesity increases the risk of liver cancer by 4.5 folds and is expected to become a leading cause of liver cancer in the US in the future. We recently showed that lipopolysaccharide (LPS) from gut bacteria and its receptor, Toll-Like Receptor 4 (TLR4), promote liver cancer driven by chronic injury. Furthermore, TLR4 ligands LPS and HMGB1 increase in obesity, and fatty livers have higher responsiveness towards LPS. Altogether, these results suggest that TLR4 may contribute to obesity-driven hepatocarcinogenesis. The objectives of this proposal are (1) to study the mechanisms by which obesity promotes liver cancer with a particular focus on the TLR4 pathway, and (2) to further the training of the minority applicant to allow him to become an independent investigator in cancer research. The immediate career goal of the principal investigator (PI) is to acquire the skills, credentials, and preliminary results necessary to successfully obtain independent funding. His long-term goal is to make relevant contributions to the understanding, prevention, and treatment of cancer. The PI has trained as a physician and has conducted basic research in obesity and liver diseases. He plans to bring together these two areas of expertise to investigate how obesity promotes liver cancer. This is a new area of investigation, which will provide him the basis for a future independent research program. The PI will gain the needed skills in three different ways: (1) Through training from his mentors, Drs. Schwabe and Wang, two well-established researchers in GI and liver diseases and cancer, and an advisory committee that includes leading cancer, obesity and Toll-like signaling experts. (2) Through formal coursework to enhance his scientific training, grant writing skills, and skills for an independent career. (3) Through presentation of hs results at external scientific meetings, networking in the Tumor Microenvironment scientific community, and publication in high impact journals. The PI will train at Columbia University, a world leading institution in biomedical research, which has a well-developed program to support its scientists and promote their career development. This scientific proposal will investigate how obesity promotes liver cancer, a question that falls within one of NCI's Provocative Questions: "How does obesity contribute to cancer risk?" The proposal will characterize the contribution of TLR4 to obesity-driven HCC in three separate Aims, which investigate: the contribution of TLR4 to obesity-driven HCC (Aim 1), the TLR4-expressing cell type that promotes HCC (Aim 2), and the TLR4 ligand that promotes HCC (Aim 3). The proposal employs cutting edge technology such as novel Cre-transgenic mice for deletion in specific hepatic cell populations, and novel transgenic mice for conditional ablation of TLR4. Results from the proposed studies will provide a better understanding of how obesity promotes liver cancer and may point to targets for treatment.

描述（由申请人提供）：肝细胞癌（HCC）是全世界癌症死亡的第三大原因。西班牙裔和黑人的肝癌发病率是白人的 2 至 4 倍。肥胖会使患肝癌的风险增加4.5倍，预计未来将成为美国肝癌的主要原因。我们最近发现，来自肠道细菌的脂多糖 (LPS) 及其受体 Toll 样受体 4 (TLR4) 会促进慢性损伤引起的肝癌。此外，肥胖时TLR4配体LPS和HMGB1增加，脂肪肝对LPS有更高的反应性。总而言之，这些结果表明 TLR4 可能有助于肥胖引起的肝癌发生。该提案的目标是（1）研究肥胖促进肝癌的机制，特别关注 TLR4 通路，以及（2）进一步培训少数人 申请人允许他成为癌症研究的独立调查员。首席研究员 (PI) 的近期职业目标是获得技能、证书和 成功获得独立资助所需的初步结果。他的长期目标是为癌症的理解、预防和治疗做出相关贡献。 PI 接受过医生培训，并在肥胖和肝脏疾病方面进行了基础研究。他计划将这两个领域的专业知识结合起来，研究肥胖如何促进肝癌。这是一个新的研究领域，这将为他未来的独立研究计划奠定基础。 PI 将通过三种不同的方式获得所需的技能：（1）通过导师 Drs. 的培训。 Schwabe 和 Wang 是两位在胃肠道、肝脏疾病和癌症方面颇有建树的研究人员，以及一个由领先的癌症、肥胖和 Toll 类信号传导专家组成的咨询委员会。 (2) 通过正规课程来加强他的科学训练，授予写作技能和独立职业的技能。 (3) 通过在外部科学会议上展示 hs 结果、在肿瘤微环境科学界建立联系以及在高影响力期刊上发表。 PI 将在哥伦比亚大学接受培训，哥伦比亚大学是世界领先的生物医学研究机构，该大学拥有完善的计划来支持科学家并促进他们的职业发展。这项科学提案将调查肥胖如何促进肝癌，这个问题属于 NCI 的挑衅性问题之一：“肥胖如何增加癌症风险？”该提案将在三个不同的目标中描述 TLR4 对肥胖驱动的 HCC 的贡献，分别研究：TLR4 对肥胖驱动的 HCC 的贡献（目标 1）、促进 HCC 的 TLR4 表达细胞类型（目标 2）以及促进 HCC 的 TLR4 配体（目标 3）。该提案采用了尖端技术，例如用于删除特定肝细胞群的新型 Cre 转基因小鼠，以及用于条件性消除 TLR4 的新型转基因小鼠。拟议研究的结果将有助于更好地了解肥胖如何促进肝癌，并可能指出治疗目标。