Mechanisms of radiation-induced tumor cell death and survival in cervical cancer

项目摘要 所附职业发展奖的目的是准备斯蒂芬妮Markovina，医学博士，博士过渡 作为一名研究肿瘤细胞死亡和存活的医生科学家， 辐射Markovina博士以优异的成绩毕业于华盛顿大学生物学专业， 通过威斯康星州的医学科学家培训计划的大学医学和研究生学位。后 在完成放射肿瘤学的临床实习后，她加入了华盛顿大学的教师队伍， 在加里·西尔弗曼博士的实验室工作她已经证明，SERPINB 3，一个成员， 丝氨酸蛋白酶抑制剂超家族介导宫颈癌细胞对辐射的抗性。她 提出研究这种细胞保护的机制，并检验SERPINB 3阻止细胞凋亡的假设。 IR后溶酶体介导的细胞死亡作为先天和/或获得性防御机制。 华盛顿大学医学院是Markovina博士发展剩余技能的理想场所 这是过渡到独立和回答这些关键问题所必需的。辐射领域的专业知识 肿瘤学系和校园范围内，以及强大的研究资源促进了合作 环境，产生了一些最有影响力的生物医学研究。西尔弗曼博士发现 SERPINB 3基因座，并且已经表征了人类细胞内丝氨酸蛋白酶抑制剂的各种重要功能。 生理学和疾病，以及它们在调节细胞死亡机制中的作用。因此，这种专业知识沿着 西尔弗曼博士在培养年轻科学家方面的记录使他成为这项提议的理想导师。博士 Markovina将参加研究生水平的课程，在当地和国际会议上展示她的作品， 与西尔弗曼博士和他的团队密切合作，以发展细胞死亡的关键知识和技术技能 机制、成像技术和动物肿瘤模型。 博士Markovina将她早期的职业生涯奉献给了癌症研究，并开辟了一条独特的道路 成为该领域为数不多的内科科学家之一。她发现 宫颈癌细胞中SERPINB 3的敲除导致较低的增殖率，并使细胞显著地 对IR和溶酶体介导的坏死更敏感。通过 她将1）确定SERPINB 3对IR的细胞保护机制，2）测试 假设SERPINB 3通过靶向溶酶体组织蛋白酶调节IR诱导的肿瘤细胞死亡，和3） 确定SERPINB 3是否作为促进肿瘤生长、转移和存活的癌蛋白发挥作用。 面对放射治疗。Markovina博士的总体目标是更好地了解细胞死亡的机制 以及癌细胞对电离辐射的反应中的存活，这对于开发改进的疗法至关重要。 她的动机不仅是她自己的病人接受放射治疗的宫颈癌，但大致 三分之二的癌症患者将接受放射治疗作为癌症治疗的一部分。

PROJECT SUMMARY The enclosed career development award is designed to prepare Stephanie Markovina, MD, PhD to transition to independence as a physician scientist studying tumor cell death and survival in response to ionizing radiation. Dr. Markovina graduated with honors in Biology from Washington University, then obtained her medical and graduate degrees through the University of Wisconsin's Medical Scientist Training Program. After finishing clinical residency in radiation oncology, she joined the faculty at Washington University, and has become embedded in Dr. Gary Silverman's laboratory. She has demonstrated that SERPINB3, a member of the serine protease inhibitor superfamily, mediates resistance to radiation in cervical cancer cells. She proposes to investigate the mechanism of this cytoprotection and test the hypothesis that SERPINB3 prevents lysosome-mediated cell death following IR as an innate and/or acquired defense mechanism. Washington University School of Medicine is the ideal setting for Dr. Markovina to develop the remaining skills necessary to transition to independence and to answer these critical questions. Expertise within the Radiation Oncology Department and campus wide, as well as robust research resources facilitate a collaborative environment that has produced some of the most impactful biomedical research. Dr. Silverman discovered the SERPINB3 locus, and has since characterized various important functions of the intracellular serpins in human physiology and disease, and their role in regulation of cell death mechanisms. Thus, this expertise along with his track record of training young scientists make Dr. Silverman an ideal mentor for this proposal. Dr. Markovina will take graduate level courses, present her work locally and at international meetings, and work closely with Dr. Silverman and his group in order to develop key knowledge and technical skills in cell death mechanisms, imaging techniques and animal tumor models. Dr. Markovina has dedicated her early professional career to cancer research and navigated a unique path through radiation oncology to become one of the few physician scientists in the field. She has found that knock-out of SERPINB3 in cervix cancer cells results in a lower proliferation rate, and renders cells significantly more sensitive to IR and to lysosome mediated necrosis in response to severe cell stress. Through the proposed research she will 1) determine the mechanism of SERPINB3 cytoprotection against IR, 2) test the hypothesis that SERPINB3 regulates IR-induced tumor cell death by targeting lysosomal cathepsins, and 3) determine whether SERPINB3 functions as an oncoprotein promoting tumor growth, metastasis and survival in the face of radiation treatment. Dr. Markovina's overall goal is to better understand mechanisms of cell death and survival in cancer cells in response to ionizing radiation, which is critical to developing improved therapies. Her motivation is not only her own patients undergoing radiation therapy for cervical cancer, but the roughly two-thirds of all patients with cancer who will receive radiation as part of their cancer management.