Exploiting myeloma proteome remodeling to extend proteasome inhibitor efficacy

项目摘要/摘要 这份促进多样性的NCI补编旨在支持奥黛丽女士的职业发展 岸下，该大学化学与化学生物学研究生项目的二年级学生 加利福尼亚州，旧金山。岸下是拉丁裔，是第一代大学生， 在加州州立大学洛杉矶分校以优异的成绩完成了她的本科学业。这个 附录与R01 CA226851有关，其PI为Arun Wiita，MD，PhD。副教授威塔博士 在系里。加州大学旧金山分校的实验室医学部主任将担任岸下女士这项提议的主要导师。 补编的研究计划与R01的目标2直接相关，R01的目标2侧重于研究 在血癌多发性骨髓瘤中的选择性剪接。特别是，R01中这一目标的一个主要目标是 识别调节剪接的新方法，这些方法可能有益于扰乱骨髓瘤的生物学或潜在地 作为一种治疗方法。在这里，Kishishita女士提出了开发新型重组蛋白融合的实验 可以进入骨髓瘤细胞并特异性地降解剪接体的亚单位的结构。她会第一个 使用GFP作为测试底物来验证这些降解器的原理，然后继续 针对靶向剪接因子设计纳米体识别元件。她将进一步使用弥撒 以光谱学为基础的蛋白质组学和信使核糖核酸序列来评估这种降解的下游影响。至 补充主要导师在骨髓瘤生物学、蛋白质组学、剪接和纳米体方面的专业知识 共同导师查尔斯·克雷克博士是加州大学旧金山分校的大学教授，有着30年的履历 良师益友。Craik博士也是蛋白质工程和蛋白质降解方面的领先专家 与这里的提案相关。Wiita博士和Craik博士与岸下女士合作，制定了一份全面的 培训计划包括体验式学习、一系列内部和外部教学课程、 有机会介绍科学工作以获得反馈，获得拨款和论文写作经验，以及 与同行和更有经验的科学家建立联系的机会。本培训计划旨在 为Kishishita女士提供独特的技能和科学经验，帮助她进入博士后学习 工作，并最终成为一个独立的教职员工职位。我们很高兴在这里完成提案，以 支持一名具有突出潜力的科学实习生的职业发展。

PROJECT SUMMARY/ABSTRACT This NCI Supplement to Promote Diversity is designed to support the career development of Ms. Audrey Kishishita, a second year student in the Chemistry and Chemical Biology Graduate Program at the University of California, San Francisco. Ms. Kishishita is of Latina descent and a first-generation college student who completed her undergraduate studies with high accolades at California State University-Los Angeles. The supplement is related to R01 CA226851, whose PI is Arun Wiita, MD, PhD. Dr. Wiita, an Associate Professor in the Dept. of Laboratory Medicine at UCSF, will serve as Ms. Kishishita's primary mentor for this proposal. The research plan of the Supplement directly relates to Aim 2 of the R01, which is focused on studying the role of alternative splicing in the blood cancer multiple myeloma. Specially, a major goal of this Aim in the R01 is to identify new ways to modulate splicing that may be beneficial either to perturb myeloma biology or potentially as a therapeutic. Here, Ms. Kishishita proposes experiments to develop novel recombinant protein fusion constructs that can enter myeloma cells and specifically degrade subunits of the spliceosome. She will first work to validate the principle of these degraders using GFP as a test substrate and then move on to engineering nanobody recognition elements for targeted splicing factors. She will further use mass spectrometry-based proteomics and mRNA-seq to evaluate downstream effects of this degradation. To complement the expertise of the primary mentor in myeloma biology, proteomics, splicing, and nanobody engineering, the co-mentor, Dr. Charles Craik, is a University Professor at UCSF with a >30 year track record of mentorship. Dr. Craik is also a leading expert in protein engineering and protein degradation, directly relevant to the proposal here. Drs. Wiita and Craik have worked with Ms. Kishishita to craft a comprehensive training plan including experiential learning, a series of both internal and external didactic courses, opportunities to present scientific work to receive feedback, experience in grant- and paper-writing, and opportunities for networking with peers and more experienced scientists. This training plan is designed to provide Ms. Kishishita with a unique skillset and scientific experience to carry her forward into her post-doctoral work and ultimately into an independent faculty position. We are excited to complete the proposal here to support the career development of a scientific trainee with outstanding potential.