Exploiting myeloma proteome remodeling to extend proteasome inhibitor efficacy

利用骨髓瘤蛋白质组重塑来延长蛋白酶体抑制剂的功效

• 批准号: 10308238
• 负责人: Arun P. Wiita
• 金额: $ 5.53万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308238
• 关键词: Active Learning; Alternative Splicing; American; Automobile Driving; Award; Binding; Biological Response Modifier Therapy; Biology; CRISPR screen; California; Cell physiology; Cells; Chemicals; Chemistry; Chimeric Proteins; Complement; Complex; Data; Development; Diagnosis; Disease; Disease remission; Doctor of Philosophy; Elements; Engineering; Essential Genes; Faculty; Feedback; First Generation College Students; Fostering; Future; Genetic; Goals; Grant; HIV; Hematopoietic Neoplasms; In Vitro; Laboratories; Latina; Los Angeles; Malignant Neoplasms; Mass Spectrum Analysis; Medicine; Mentors; Mentorship; Messenger RNA; Molecular Machines; Multiple Myeloma; Nature; Paper; Parents; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Physiological; Plasma Cells; Play; Positioning Attribute; Post-Translational Protein Processing; Postdoctoral Fellow; Proteasome Inhibitor; Protein Engineering; Proteome; Proteomics; Publishing; RNA Splicing; Reagent; Recombinant Fusion Proteins; Recombinant Proteins; Recombinants; Research; Research Training; Resistance; Resistance development; Role; San Francisco; Scientist; Series; Specificity; Spliceosomes; Students; System; Testing; Therapeutic; Training; Universities; Western Blotting; Work; Writing; Yeasts; antibody engineering; base; cancer cell; cancer therapy; career development; design; experience; experimental study; genome-wide; graduate student; in vitro Model; inhibitor/antagonist; knock-down; mRNA Precursor; mRNA sequencing; mid-career faculty; nanobodies; novel; peer; phosphoproteomics; professor; programs; protein degradation; proteostasis; response; small molecule; therapy resistant; tool; transcriptome sequencing; transcriptomics; ubiquitin-protein ligase; undergraduate student

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.

项目总结/摘要 这个NCI补充，以促进多样性的目的是支持奥黛丽女士的职业发展 Kishishita是该大学化学和化学生物学研究生课程的二年级学生 来自加州的弗朗西斯科。岸下女士是拉丁裔，是第一代大学生， 在加州州立大学洛杉矶分校以优异成绩完成了本科学业。的 补充与R 01 CA 226851相关，其PI为Arun Wiita，MD，PhD。Wiita博士，副教授 在部门。加州大学旧金山分校的实验医学博士，将担任岸下女士的主要导师，为这一建议。 补编的研究计划与研究报告01的目标2直接相关，其重点是研究 选择性剪接在血癌多发性骨髓瘤中的作用。特别是，R 01中的这一目标的主要目标是 确定调节剪接的新方法，这些方法可能有益于干扰骨髓瘤生物学或潜在地 作为一种治疗。在这里，岸下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降解剪接体亚基的构建体。她会先 使用GFP作为测试底物，验证这些降解剂的原理，然后继续 工程化用于靶向剪接因子的纳米抗体识别元件。她将进一步利用质量 基于光谱的蛋白质组学和mRNA-seq来评估这种降解的下游影响。到 补充主要导师在骨髓瘤生物学、蛋白质组学、剪接和纳米抗体方面的专业知识 工程，共同导师，博士查尔斯克雷克，是一个大学教授在加州大学旧金山分校与超过30年的跟踪记录 导师制Craik博士也是蛋白质工程和蛋白质降解的领先专家，直接 与这里的提议有关。Wiita博士和Craik博士与Kishishita女士合作， 培训计划，包括体验式学习，一系列内部和外部教学课程， 有机会提出科学工作，以获得反馈，在赠款和论文写作的经验， 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 为岸下女士提供独特的技能和科学经验，使她能够继续从事博士后工作 工作，并最终成为一个独立的教师职位。我们很高兴在这里完成提案， 支持具有杰出潜力的科学培训生的职业发展。