The Renin-Angiotensin System in Hepatitis and Hepatoma

描述（由申请人提供）：玛丽Maluccio是一个委员会认证的外科肿瘤学家。她最近在印第安纳州大学获得了终身教职。她的近期职业目标是建立一个富有成效的实验室研究环境。她的长期职业目标包括：1）基于实验室观察的领先临床研究方案，2）增加她在癌症研究界的存在。 在致力于支持转化研究方法的学术环境中集中精力，她认为她有潜力将坚实的R 01资助申请整合到一起，用于研究方案，这不仅有助于回答有关癌症生物学的问题，而且改变了我们治疗癌症患者的方式。她的临床和基础科学兴趣目前集中在研究调查肝细胞癌生物学和恶性表型的基质细胞的影响。原发性肝癌是一个全球性的问题，治疗方法有限，病理生理学仍不清楚。研究肾素-血管紧张素系统在肝炎和肝细胞癌发展中的作用是完全新颖的。该提案的主要目的是1）使用已建立的肝炎相关癌症的临床前模型来研究与肝细胞肿瘤发生相关的基质影响和分子机制，2）研究肾素-血管紧张素系统的影响和AII受体信号转导对肿瘤生长的影响3）确定肾素-血管紧张素系统的表达水平和定位。肝炎和肝细胞癌患者的肝组织和肿瘤中的血管紧张素系统元件，和4）确定在肾素-血管紧张素系统和肿瘤生长之间是否存在将暴露新的治疗靶点的联系。本研究需要使用来自沿着一系列肝炎相关肝病（0期至4期）患者的人肝脏标本，包括已发生肝细胞癌的肝炎患者。临床前模型涉及将人肝炎衍生的肝细胞癌异种移植到免疫缺陷小鼠中。

DESCRIPTION (provided by applicant): Mary Maluccio is a board certified surgical oncologist. She has recently secured a tenure track position at Indiana University. Her immediate career goal is to set up a productive laboratory research environment. Her long term career goals include: 1) leading clinical research protocols based on observations made in the laboratory and 2) increasing her presence within the cancer research community. With a concentrated effort in an academic environment committed to supporting a translational research approach, she feels that she has the potential to put together solid R01 grant applications for research protocols that will not only help answer questions about cancer biology, but change the way we treat cancer patients. Her clinical and basic science interests currently focus on studies investigating hepatocellular carcinoma biology and the impact of the stromal cells on the malignant phenotype. Primary liver cancer is a worldwide problem with limited therapies and a pathophysiology that remains unclear. An investigation into the role of the renin-angiotensin system in hepatitis and the development of hepatocellular cancer is something completely novel. The primary objectives of the proposal are 1) to use an established preclinical model of hepatitis associated cancer to investigate the stromal influence and molecular mechanisms associated with hepatocellular tumorigenesis, 2) to investigate the influence of the renin-angiotensin system and the consequences of AII receptor signal transduction on tumor growth 3) determine the level of expression and localization of renin-angiotensin system elements in liver tissue and tumors of patients with hepatitis and hepatocellular cancer, and 4) to determine if there is a link between the renin-angiotensin system and tumor growth that would expose a novel therapeutic target. This study entails the use of human liver specimens from the patients along a continuum of hepatitis related liver disease (stage 0 through stage 4), including patients with hepatitis who have developed hepatocellular carcinoma. The preclinical model involves a human hepatitis derived hepatocellular carcinoma xenograft into an immunodeficient mouse.