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

项目概要 随附的职业发展奖旨在帮助 Stephanie Markovina 医学博士、博士做好过渡准备 作为一名医师科学家独立研究电离反应下的肿瘤细胞死亡和存活 辐射。 Markovina 博士以优异的成绩毕业于华盛顿大学生物学系，然后获得了她的学位 通过威斯康星大学医学科学家培训计划获得医学和研究生学位。之后 完成放射肿瘤学临床住院医师培训后，她加入了华盛顿大学，并在 融入加里·西尔弗曼博士的实验室。她证明了 SERPINB3 的成员 丝氨酸蛋白酶抑制剂超家族，介导宫颈癌细胞对辐射的抵抗力。她 提议研究这种细胞保护的机制并检验 SERPINB3 阻止的假设 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 过渡到独立并回答这些关键问题是必要的。辐射领域的专业知识 肿瘤学系和整个校园以及强大的研究资源促进了协作 产生了一些最具影响力的生物医学研究的环境。西尔弗曼博士发现 SERPINB3 位点，并从此表征了人类细胞内丝氨酸蛋白酶抑制剂的各种重要功能 生理学和疾病及其在细胞死亡机制调节中的作用。因此，这种专业知识以及 西尔弗曼博士在培训年轻科学家方面的记录使他成为该提案的理想导师。博士。 马尔科维纳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，并工作 与 Silverman 博士及其团队密切合作，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。 Markovina 博士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 通过放射肿瘤学成为该领域为数不多的医师科学家之一。她发现 敲除宫颈癌细胞中的 SERPINB3 会导致增殖率降低，并使细胞显着恶化 对IR和溶酶体介导的坏死更敏感，以应对严重的细胞应激。通过 在拟议的研究中，她将 1) 确定 SERPINB3 针对 IR 的细胞保护机制，2) 测试 假设 SERPINB3 通过靶向溶酶体组织蛋白酶来调节 IR 诱导的肿瘤细胞死亡，以及 3) 确定 SERPINB3 是否作为癌蛋白发挥作用，促进肿瘤生长、转移和存活 面对放射治疗。 Markovina 博士的总体目标是更好地了解细胞死亡机制 以及癌细胞响应电离辐射的存活率，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患者接受宫颈癌放射治疗，而且大致是 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.