Role of IRF-1 in Tumor Suppression of Breast Cancer

描述（由申请人提供）：申请人希望成为一名杰出的外科科学家。这份建议描述了一个为期5年的培训计划，将提供说教式教学、新方法的获取、与其他科学家的互动、职业指导和监督研究，以使他成为一名优秀的研究者。在过去三年里，他在匹兹堡大学的Timothy R. Billiar和Walter Storkus的指导下进行了高质量的研究。为了发展他的研究事业，他希望更多的时间投入到基础研究中，这将通过K08奖成为可能。该计划将促进两个学科的指挥，凋亡/细胞周期调控和肿瘤免疫学。billar博士是细胞凋亡研究的公认领导者，Storkus博士是肿瘤免疫学的公认领导者。申请人的研究与这两者都有很强的联系。研究将集中在IRF-1在体外和体内对乳腺癌肿瘤抑制中的作用。在初步研究中，已经构建了IRF-1重组腺病毒（Ad-IRF-1），并证实其在小鼠和人乳腺细胞中具有功能性表达。已发现Ad-IRF-1能抑制乳腺癌细胞的生长，但不能抑制非恶性乳腺细胞的生长，并且在体外和体内均发现了乳腺癌的抑瘤作用。其抗肿瘤作用可能与细胞凋亡、细胞周期和免疫等因素有关。利用Ad-IRF-1和体外和体内模型，将评估IRF-1在乳腺癌特异性生长抑制和增强肿瘤免疫原性中的作用。具体目的包括：1)确定细胞凋亡和细胞周期效应在体外和体内诱导的肿瘤特异性生长抑制中的直接作用；2)评估Ad-IRF-1感染肿瘤细胞在预防和治疗小鼠肿瘤模型中的增强免疫原性；3)确定IRF-1诱导的细胞凋亡在乳腺癌免疫应答中的作用。本研究结合导师的优势，明确了IRF-1在乳腺Ca中细胞凋亡和肿瘤免疫原性的抗肿瘤机制及其相互作用。

DESCRIPTION (provided by applicant): The applicant seeks to become an outstanding surgeon-scientist. This proposal describes a 5 year training program that will provide didactic teaching, acquisition of new methods, interactions with other scientists, career guidance, and supervised research to develop him into a superb investigator. He has performed high-quality research at the University of Pittsburgh under the mentorship of Timothy R. Billiar and Walter Storkus for the last three years. To develop his research career, he seeks more time commitment to basic research which would be made possible by the K08 award. The program will promote the command of two disciplines, apoptosis/cell cycle regulation and tumor immunology. Dr. Billiar is a recognized leader in apoptosis studies, and Dr. Storkus is a recognized leader in tumor immunology. The applicant's research has strong links to both. Research will focus on the role of IRF-1 in tumor suppression of breast cancer in vitro and in vivo. In preliminary research recombinant adenovirus for IRF-1 (Ad-IRF-1) has been constructed and confirmed to have functional expression in mouse and human breast cells. Ad-IRF-1 has been found to inhibit the growth of breast cancer cells, but not non-malignant breast cells, and tumor suppression of breast cancer has been found in vitro and in vivo. The antitumor effect seems to be mediated by apoptotic, cell cycle, and immune factors. Using Ad-IRF-1 and in vitro and in vivo models the role of IRF-1 in breast cancer specific growth inhibition and enhanced tumor immunogenicity will be evaluated. The specific aims include: 1) Determine the direct role of apoptosis and cell cycle effects in IRF-1 induced cancer-specific growth inhibition in vitro and in vivo, 2) Evaluate the enhanced immunogenicity of tumor cells infected with Ad-IRF-1 in prophylactic and therapeutic murine tumor models, and 3) Determine the role of IRF-1 induced apoptosis in the breast cancer immune response. This research combines the strengths of the mentors, and defines the antitumor mechanism of apoptosis and tumor immunogenicity and the interaction between them in breast Ca by IRF-1.