TLR4 in obesity-driven liver cancer

描述(申请人提供)：肝细胞癌是全球第三大癌症死亡原因。西班牙裔和黑人的肝癌发病率是白人的2到4倍。肥胖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。我们最近发现肠道细菌的脂多糖及其受体Toll样受体4(TLR4)可促进慢性损伤所致的肝癌的发生。此外，TLR4配体脂多糖和HMGB1在肥胖中增加，脂肪肝对脂多糖的反应性更高。综上所述，这些结果表明TLR4可能参与了肥胖导致的肝癌的发生。这项建议的目的是(1)研究肥胖促进肝癌的机制，特别是TLR4途径，以及(2)进一步训练少数人 申请者允许他成为癌症研究的独立调查员。首席调查员(PI)的直接职业目标是获得技能、证书和 取得成功获得独立资金所必需的初步结果。他的长期目标是为了解、预防和治疗癌症做出相关贡献。PI接受过医生培训，并进行过肥胖症和肝病的基础研究。他计划将这两个领域的专业知识结合起来，研究肥胖是如何促进肝癌的。这是一个新的调查领域，这将为他未来的独立研究计划提供基础。PI将通过三种不同的方式获得所需的技能：(1)通过他的导师Schwabe博士和Wang博士的培训，Schwabe博士和Wang博士是胃肠道、肝脏疾病和癌症方面的两位知名研究人员，以及一个包括领先的癌症、肥胖症和Toll-like信号专家的咨询委员会。(2)通过正规的课程学习，提高他的科学训练、写作技能和独立职业技能。(3)通过在外部科学会议上发表hs成果，在肿瘤微环境科学界建立网络，并在高影响力期刊上发表文章。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，该大学有一个完善的项目来支持其科学家并促进他们的职业发展。这项科学提案将调查肥胖是如何促进肝癌的，这个问题属于NCI的一个具有挑衅性的问题：“肥胖如何导致癌症风险？”该提案将从三个不同的目标来描述TLR4对肥胖驱动的肝癌的贡献，这三个目标调查：TLR4对肥胖驱动的肝癌的贡献(目标1)，促进肝癌的TLR4表达的细胞类型(目标2)，以及促进肝癌的TLR4配体(目标3)。该提议采用了尖端技术，例如用于在特定肝细胞群中缺失的新型Cre转基因小鼠，以及用于条件切除TLR4的新型转基因小鼠。拟议的研究结果将提供更好的了解肥胖是如何促进肝癌的，并可能指出治疗的目标。

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.