Determination of P21 downstream signaling in the toxicity of MC and DMC DNA interstrand crosslinks (Student: Kameza Harun)

摘要： 这份《促进多样性的研究补充文件》的主要目标是 与健康相关的研究“是考察立体异构体的结构之间的关系 丝裂霉素C和脱氨酰丝裂霉素C形成的DNA链间交联物 这些药物的分子机制。丝裂霉素C(MC)是一种抗癌药物，目前用于 治疗胃癌、肛门癌和肺癌。MC大分子ICL的C_1‘’立体构型 为R(α-icl)。相比之下，脱氨甲酰丝裂霉素C(DMC)是MC的衍生物，缺乏O10 氨甲酰基，生成S立体异构体ICl(β-ICl)。科学的前提是 建议的研究是ICL构成了细胞毒作用的分子基础 丝裂霉素类。中心假设是α和β局部dna结构的差异- ICL负责MC和DMC触发的不同生化反应。在……里面 特别是，与MC相反，由DMC处理产生的dna加合物(-icl)迅速激活 一条不依赖于p53的细胞死亡途径。因此，MC-DMC的研究为下一步的研究提供了理想的模型 确定在存在或存在的情况下决定细胞信号结果的结构特征 缺乏功能正常的P53途径。由于P53肿瘤抑制基因经常在 人类癌症，需要识别导致细胞死亡或细胞周期停滞的药物和途径 与P53无关的问题值得大力关注。在父项目的范围内，这 用于促进健康相关研究多样性的补充将用于培训候选人， Kameza Harun to：1：合成含有α/βICL的寡核苷酸；2：用 α/βICL和提取蛋白质；3：验证下游信号分子，如细胞周期蛋白 B1/cdk1，参与α或β诱导的p21信号通路。 ICL.Kameza的长期目标是成为肿瘤学的临床研究人员。培训和 拟议的活动将增加Kameza获得MD-PhD项目的机会，通过促进 关键的技术和专业技能。随着Kameza获得对这项研究的新接触 环境，她会变得更自在地与其他科学家互动，分享她的 工作。她将为加入一个研究实验室做好充分准备。为了进一步加强Kameza的 竞争力，她将在会议上展示她的研究成果，并发表至少一篇 手稿。她还将接受Edgardo Sanabria-Valentin博士的职业建议 PRISM副项目主任兼健康前职业顾问。他将协助卡米扎 考虑长期的职业目标和实现这些目标所需的技能。

Summary: The overarching goal of the parent proposal for this “research supplement to promote diversity in health-related research” is to investigate the relationship between the structure of stereoisomeric DNA Interstrand Crosslinks (ICLs) formed by Mitomycin C and Decarbamoylmitomycin C and the molecular mechanisms of these drugs. Mitomycin C (MC) is an anticancer drug currently used to treat stomach, anal and lung cancers. The stereochemical configuration at C1’’ of MC major ICL is R (α-ICL). In contrast, Decarbamoylmitomycin C (DMC), a derivative of MC lacking the O10 carbamoyl group, generates the S stereoisomeric ICL (β-ICL). The scientific premise of the proposed research is that ICLs constitute the molecular basis for the cytotoxic effects of mitomycins. The central hypothesis is that differences in the local DNA structures of the α and β- ICLs are responsible for the distinct biochemical responses triggered by MC and DMC. In particular, contrary to MC, the DNA-adducts generated by DMC treatment (-ICL) rapidly activate a p53-independent cell death pathway. Thus, the study MC-DMC provides an ideal model for identifying structural features determining the cell signaling outcome in the presence or the absence of a functioning p53 pathway. Since p53 tumor suppressor is frequently mutated in human cancers, the need to identify drugs and pathways that induce cell death or cell cycle arrest independently of p53 deserves substantial attention. Within the scope of the parent project, this supplement to promote diversity in health-related research will be used to train the candidate, Kameza Harun to: 1: Synthesize oligonucleotides containing α/β ICLs; 2: Transfect cells with the α/β ICLs and extract proteins; 3: Validate the downstream signaling molecules, such as cyclin B1/Cdk1, involved in the p21 signaling pathway triggered by the presence of either the α or β- ICL. Kameza’s long-term goal is to become a clinical researcher in oncology. The training and activities proposed will improve Kameza’s chances to access MD-PHD programs by fostering crucial technical and professional skills. As Kameza gains new exposure to the research environment, she will become more comfortable interacting with other scientists and sharing her work. She will be fully prepared to join a research laboratory. In order to further enhance Kameza’s competitiveness, she will present her research findings at conferences and publish at least one manuscript. She will also receive career advisement from Dr Edgardo Sanabria-Valentin, the PRISM Associate Program Director and Pre-Health Career Advisor. He will assist Kameza in considering long-term career goals and the skills needed to achieve them.