Gut microbiota-derived signaling in liver carcinogenesis and cancer treatment

肠道微生物群衍生的肝癌发生和癌症治疗中的信号传导

• 批准号: 10682541
• 负责人: YING HU
• 金额: $ 8.63万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10682541
• 关键词: Affect; Animal Cancer Model; Apoptosis; Applications Grants; Bile Acids; Cancer Research Project; Cell model; Chemicals; Colon; Colon Carcinoma; Disease; Fatty Acids; Funding; Goals; Grant; Hepatocarcinogenesis; Lead; Liver; Malignant Neoplasms; Malignant neoplasm of liver; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Compound; Organ; Outcome Study; Pathway interactions; Peer Review; Positioning Attribute; Prevention; Preventive; Primary carcinoma of the liver cells; Publications; Research; Role; Signal Transduction; Small Business Innovation Research Grant; Specialist; Tretinoin; Tumor Suppressor Proteins; Volatile Fatty Acids; Work; alternative treatment; anti-cancer; anticancer research; cancer cell; cancer therapy; carcinogenesis; career; combat; effective therapy; gut microbes; gut microbiota; gut-liver axis; liver inflammation; mouse model; novel strategies; programs; treatment strategy

PROJECT ABSTRACT Hepatocellular carcinoma (HCC) is a deadly disease with limited treatment options. Therefore, there is an urgent need to develop alternative treatments for liver cancer, which is the primary goal of this application under the existing research program (1R01 CA222490). An effective cancer treatment strategy should target the pathways by which cancer arises in the first place. Emerging evidence also reveals that gut microbiota- derived signaling is not only implicated in colon cancer but also affects hepatic inflammation and liver carcinogenesis. Thus, to develop targeted strategies for liver cancer treatment, it is important to uncover the mechanism of gut-derived signaling in the liver. The Research Specialist (Dr. Ying Hu) and Unit Director (Dr. Yu-Jui Yvonne Wan) have worked together for the past 8 years, starting in 2011, and have generated 11 peer- reviewed publications in cancer research. Dr. Wan's research programs have been sponsored by a long-term, continuously funded R01 grant, NCI R01 CA053596 (1991-2016), and a cooperative U grant NCI U01 CA179582 (2014-2019, lead PI), NCI R01 CA222490 (2018-2023), and NIDDK R01 DK092100 (2011-2017). Dr. Hu has participated in all of these above-mentioned projects and has a thorough understanding of how Dr. Wan's cancer research program evolved. Dr. Hu has unique expertise in the gut-liver axis as well as in orthotopic liver and colon cancer animal models. She has conducted extensive research using both liver and colon cancer cells and mouse models to study the pathways controlled by natural compounds present in the gut and liver, including bile acids (BAs), retinoic acid (RA), and short-chain fatty acids (SCFAs). Our research program (1R01 CA222490) focuses on these natural chemicals, which are directly or indirectly produced by gut microbes and are able to induce the tumor suppressor miR-22 in the liver and colon. Thus, miR-22 and its inducers can not only induce cancer cell apoptosis and arrest, but also provide a preventive means to stop cancer reoccurrence, leading to an effective treatment strategy. The applicant, Ying Hu, has worked closely with Dr. Wan in developing plans to achieve the following goals: Aim 1 studies the mechanism by which miR- 22 has an anti-cancer effect by studying the downstream targets of miR-22. Aim 2 examines the role of miR-22 in liver cancer treatment using orthotopic liver cancer mouse models. Aim 3 analyzes the role of miR-22 inducers in liver cancer treatment. Successful completion of the proposed studies will lead to novel strategies to treat liver cancer as well as colon cancer via miR-22 targeted pathways. The funds freed-up due to funding of the current application will allow us to develop other collaborative programs that will lead to submission of an SBIR grant application to advance Dr. Hu's career goals. Dr. Wan is the primary support Unit Director who will continue to work with Dr. Hu to plan, direct, and execute the proposed research.

项目摘要 肝细胞癌（HCC）是一种治疗选择有限的致命疾病。因此，有一个 迫切需要开发肝癌的替代治疗方法，这是本申请的主要目标 根据现有的研究计划（1 R 01 CA 222490）。有效的癌症治疗策略应该针对 癌症最初产生的途径。新出现的证据还表明，肠道微生物群- 衍生的信号传导不仅与结肠癌有关，而且还影响肝脏炎症和肝脏 致癌作用因此，为了开发肝癌治疗的靶向策略，重要的是要揭示 肝脏中肠源性信号传导的机制。研究专家（胡英博士）和单位主任（胡博士）。 Yu-Jui Yvonne Wan）从2011年开始在过去的8年里一起工作，并产生了11个同行- 回顾癌症研究的出版物。万博士的研究项目得到了一个长期的， 连续资助的R 01赠款，NCI R 01 CA 053596（1991-2016）和合作U赠款NCI U 01 CA 179582（2014-2019，主要PI）、NCI R 01 CA 222490（2018-2023）和NIDDK R 01 DK 092100（2011-2017）。 博士胡先生曾参与上述所有项目，并深入了解胡博士如何参与该等项目。 Wan的癌症研究计划不断发展。胡博士在肠肝轴以及 原位肝癌和结肠癌动物模型。她进行了广泛的研究， 结肠癌细胞和小鼠模型，以研究由存在于结肠癌细胞中的天然化合物控制的途径。 肠道和肝脏，包括胆汁酸（BA）、视黄酸（RA）和短链脂肪酸（SCFA）。我们的研究 1 R 01 CA 222490是一个针对肠道直接或间接产生的天然化学物质的研究项目。 在某些情况下，它们可以在肝脏和结肠中诱导肿瘤抑制因子miR-22。因此，miR-22及其 诱导剂不仅可以诱导癌细胞凋亡和停滞，而且还提供了一种预防性的手段， 癌症复发，导致有效的治疗策略。申请人胡英曾与 与万博士一起制定计划，以实现以下目标：目标1研究miR- 通过研究miR-22的下游靶点，发现miR-22具有抗癌作用。目的2研究miR-22的作用 在使用原位肝癌小鼠模型的肝癌治疗中。目的3分析miR-22在肿瘤细胞中的作用 肝癌治疗中的诱导剂。成功完成拟议的研究将导致新的战略 通过miR-22靶向途径治疗肝癌和结肠癌。由于资金不足， 目前的应用程序将允许我们开发其他合作计划，这将导致提交一个 SBIR资助申请，以推进胡博士的职业目标。Wan博士是主要的支持单位主任， 继续与胡博士合作，计划、指导和执行拟议的研究。