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

确定 MC 和 DMC DNA 链间交联毒性中的 P21 下游信号传导（学生：Kameza Harun）

• 批准号: 10378838
• 负责人: Elise Champeil
• 金额: $ 3.17万
• 依托单位: JOHN JAY COLLEGE OF CRIMINAL JUSTICE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378838
• 关键词: Antineoplastic Agents; Apoptotic; Attention; Biochemical; Cell Cycle Arrest; Cell Death; Cells; Clinical; DNA Adducts; DNA Interstrand Crosslinking; DNA Structure; Environment; Exposure to; Fostering; Goals; Health; Human; Laboratory Research; Malignant Neoplasms; Malignant neoplasm of anus; Malignant neoplasm of lung; Manuscripts; Mitomycin C; Mitomycins; Modeling; Molecular; Mutate; Oligonucleotides; Oncology; Outcome; Parents; Pathway interactions; Pharmaceutical Preparations; Proteins; Publishing; Research; Research Personnel; Research Proposals; Scientist; Signal Pathway; Signal Transduction; Signaling Molecule; Structure; Students; TP53 gene; Toxic effect; Training; Training Activity; Work; base; career; chemotherapeutic agent; crosslink; cyclin B1; cytotoxic; genetic makeup; improved; malignant stomach neoplasm; parent project; personalized medicine; programs; response; skills; symposium; transcription factor; tumor

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.

概括： 家长提案的总体目标是“促进多样性的研究补充” 健康相关研究”是研究立体异构体结构之间的关系 由丝裂霉素 C 和去氨甲酰丝裂霉素 C 形成的 DNA 链间交联 (ICL) 以及 这些药物的分子机制。丝裂霉素 C (MC) 是目前用于治疗癌症的药物。 治疗胃癌、肛门癌和肺癌 MC 主要 ICL 的 C1'' 立体化学构型。 是 R (α-ICL)，相反，去氨甲酰丝裂霉素 C (DMC)，是缺少 O10 的 MC 衍生物。 氨基甲酰基，生成 S 立体异构 ICL (β-ICL) 的科学前提。 拟议的研究是 ICL 构成了细胞毒性作用的分子基础 丝裂霉素的中心假设是α和β-的局部DNA结构的差异。 ICL 负责 MC 和 DMC 触发的不同生化反应。 特别是，与 MC 相反，DMC 处理（-ICL）产生的 DNA 加合物迅速激活 因此，MC-DMC 研究提供了一个理想的模型。 结构特征决定细胞信号转导结果的存在或 由于 p53 肿瘤抑制因子经常发生突变，因此缺乏有效的 p53 通路。 人类癌症，需要识别诱导细胞死亡或细胞周期停滞的药物和途径 在父项目的范围内，独立于 p53 值得大量关注。 促进健康相关研究多样性的补充品将用于培训候选人， Kameza Harun：1：合成含有 α/β ICL 的寡核苷酸；2：用 α/β ICL并提取蛋白质；3：验证下游信号分子，例如细胞周期蛋白 B1/Cdk1，参与由 α 或 β- 的存在触发的 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。 拟议的活动将通过培养 随着卡米扎获得新的研究机会，关键的技术和专业技能。 环境中，她将变得更自在地与其他科学家互动并分享她的 她将为加入研究实验室做好充分准备，以进一步增强卡米扎的能力。 为了提高竞争力，她将在会议上展示她的研究成果并发表至少一篇 她还将获得埃德加多·萨纳布里亚·瓦伦丁博士（Dr Edgardo Sanabria-Valentin）的职业建议。 PRISM 副项目总监兼健康前职业顾问他将协助 Kameza 进行相关工作。 考虑长期职业目标以及实现这些目标所需的技能。