The Renin-Angiotensin System in Hepatitis and Hepatoma

描述(由申请人提供)：Mary Maluccio是一名委员会认证的外科肿瘤学家。她最近在印第安纳大学获得了终身教职。她的直接职业目标是建立一个高效的实验室研究环境。她的长期职业目标包括：1)领导基于实验室观察结果的临床研究方案；2)扩大她在癌症研究领域的影响力。 在致力于支持转化式研究方法的学术环境中，她认为自己有潜力为研究方案整合坚实的R01拨款申请，这些申请不仅有助于回答有关癌症生物学的问题，还将改变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肝细胞癌生物学和基质细胞对恶性表型的影响。原发性肝癌是一个世界性的问题，治疗方法有限，其病理生理机制尚不清楚。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一项全新的研究。该建议的主要目标是：1)使用已建立的肝炎相关癌症的临床前模型，研究与肝细胞肿瘤发生相关的间质影响和分子机制；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-血管紧张素系统元件在肝炎和肝细胞癌患者肝组织和肿瘤中的表达水平和定位；以及4)确定肾素-血管紧张素系统与肿瘤生长之间是否存在联系，从而揭示新的治疗靶点。这项研究需要使用一系列肝炎相关肝病(0期至4期)患者的人肝标本，包括发展为肝细胞癌的肝炎患者。临床前模型包括将人类肝炎衍生的肝细胞癌移植到免疫缺陷小鼠体内。

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.