TLR4 in obesity-driven liver cancer

描述（由申请人提供）：肝细胞癌（HCC）是全球第三大癌症死亡原因。西班牙裔和黑人的肝癌发生率是白人的2至4倍。肥胖使肝癌的风险增加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）促进了慢性损伤驱动的肝癌。此外，TLR4配体LPS和HMGB1在肥胖中增加，脂肪肝对LPS具有更高的反应性。总之，这些结果表明TLR4可能有助于肥胖驱动的肝癌发生。该提案的目的是（1）研究肥胖促进肝癌的机制，特别关注TLR4途径，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。主要研究者（PI）的直接职业目标是获得技能，证书， 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接受了医生培训，并进行了肥胖和肝脏疾病的基础研究。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）通过他的导师施瓦贝博士和Wang博士的培训，这两位研究人员在胃肠道和肝脏疾病以及癌症方面享有盛誉，以及一个咨询委员会，其中包括领先的癌症，肥胖和Toll样信号专家。(2)通过正式的课程，以加强他的科学训练，授予写作技能，并为一个独立的职业生涯的技能。(3)通过在外部科学会议上介绍HS结果，在肿瘤微环境科学界建立网络，并在高影响力期刊上发表。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，拥有完善的计划来支持其科学家并促进他们的职业发展。这项科学建议将调查肥胖如何促进肝癌，这个问题福尔斯属于NCI的挑衅性问题之一：“肥胖如何导致癌症风险？“该提案将在三个独立的目标中描述TLR4对肥胖驱动的HCC的贡献，这些目标调查：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，例如用于特定肝细胞群缺失的新型Cre转基因小鼠，以及用于TLR4条件性消融的新型转基因小鼠。拟议研究的结果将更好地了解肥胖如何促进肝癌，并可能指向治疗目标。

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.