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.

项目概要/摘要 NCI 促进多元化补充品旨在支持 Audrey 女士的职业发展 岸下，大学化学与化学生物学研究生项目二年级学生 加利福尼亚州、旧金山。岸下女士是拉丁裔后裔，是第一代大学生。 以优异的成绩在加州州立大学洛杉矶分校完成了本科学业。这 补充品与 R01 CA226851 相关，其 PI 是 Arun Wiita，MD、PhD。 Wiita 博士，副教授 加州大学旧金山分校检验医学系的 Kishishita 女士将担任该提案的主要导师。 该增补的研究计划与R01的目标2直接相关，重点研究角色 选择性剪接在血癌多发性骨髓瘤中的作用。特别地，R01 中这一目标的一个主要目标是 确定调节剪接的新方法，这可能有益于扰乱骨髓瘤生物学或潜在 作为一种治疗方法。岸下女士在此提出了开发新型重组蛋白融合物的实验 可以进入骨髓瘤细胞并特异性降解剪接体亚基的构建体。她首先会 使用 GFP 作为测试底物来验证这些降解剂的原理，然后继续 针对目标剪接因子设计纳米抗体识别元件。她将进一步利用质量 基于光谱分析的蛋白质组学和 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 共同导师 Charles Craik 博士是 UCSF 的大学教授，拥有超过 30 年的工作经验 的指导。 Craik 博士也是蛋白质工程和蛋白质降解领域的领先专家，直接 与此处的提案相关。博士。 Wiita 和 Craik 与 Kishishita 女士合作，制定了一份全面的报告 培训计划包括体验式学习、一系列内部和外部教学课程、 展示科学工作以获得反馈的机会、资助和论文写作的经验，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，帮助她进入博士后阶段 工作并最终获得独立的教职职位。我们很高兴能够在这里完成提案 支持具有突出潜力的科学实习生的职业发展。