Role of IRF-1 in Tumor Suppression of Breast Cancer

描述(申请人提供)：应聘者希望成为一名杰出的外科科学家。这份提案描述了一项为期5年的培训计划，该计划将提供教学、获取新方法、与其他科学家的互动、职业指导和监督研究，以将他培养成一名出色的调查员。在过去的三年里，他在蒂莫西·R·比利亚尔和沃尔特·斯托库斯的指导下，在匹兹堡大学进行了高质量的研究。为了发展他的研究事业，他寻求更多的时间致力于基础研究，这将使K08奖成为可能。该计划将促进对两个学科的掌握，即细胞凋亡/细胞周期调节和肿瘤免疫学。比利亚尔博士是公认的细胞凋亡研究领导者，斯托库斯博士是公认的肿瘤免疫学领导者。申请者的研究与这两项研究都有很强的联系。研究重点将集中在IRF-1在体外和体内抑制乳腺癌中的作用。在初步研究中，我们构建了针对IRF-1的重组腺病毒(Ad-IRF-1)，并证实其在小鼠和人乳腺细胞中均有功能表达。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，并且在体外和体内都发现了对乳腺癌的抑制作用。其抗肿瘤作用可能与细胞凋亡、细胞周期和免疫因素有关。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。其具体目的包括：1)确定细胞凋亡和细胞周期效应在IRF-1诱导的体内外肿瘤特异性生长抑制中的直接作用；2)评价Ad-IRF-1感染的肿瘤细胞在预防和治疗小鼠肿瘤模型中的增强免疫原性；以及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Mentors的优势，通过IRF-1明确了乳腺钙质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.