Deciphering non-canonical translation in high risk medulloblastoma

破译高风险髓母细胞瘤的非规范翻译

• 批准号: 10522208
• 负责人: John Prensner
• 金额: $ 22.68万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10522208
• 关键词: 5' Untranslated Regions; Advisory Committees; Area; Award; Binding; Biological Models; Cancer Biology; Cell Line; Cell Survival; Cell physiology; Cells; Cerebellum; Child; Childhood; Childhood Brain Neoplasm; Childhood Malignant Brain Tumor; Code; Complex; Computational Biology; Computer Analysis; Dana-Farber Cancer Institute; Data; Disease; Disease model; Electroporation; Environment; Evaluation; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Goals; Grant; Growth; Growth and Development function; Human; Human Genome; Human Genome Project; Immunohistochemistry; In Vitro; Institutes; Institution; Investigation; K-Series Research Career Programs; Knock-out; Knowledge; Lethal Genes; Maintenance; Malignant Neoplasms; Mediator of activation protein; Mentors; Mentorship; Messenger RNA; Modeling; Mus; Oncogenic; Oncologist; Open Reading Frames; Outcome; Pathogenesis; Patient Care; Patient-Focused Outcomes; Phenotype; Physicians; Plant Roots; Positioning Attribute; Post-Transcriptional Regulation; Proteins; Proteome; Proteomics; Regulation; Research; Research Personnel; Research Training; Role; Scientist; Serum; Support System; Techniques; Testing; Therapeutic; Time; Training; Translations; Treatment Protocols; United States National Institutes of Health; Work; Xenograft procedure; authority; cancer cell; career; career development; clinically relevant; experience; fetal; high risk; improved; in utero; in vivo; in vivo Model; innovation; instructor; medulloblastoma; medulloblastoma cell line; member; mortality; mouse model; nerve stem cell; neuro-oncology; novel; novel strategies; prefoldin; programs; relating to nervous system; research and development; skills; stem; symposium; therapeutic target; training opportunity; tumor; tumorigenesis

PROJECT SUMMARY/ABSTRACT Children with the Group 3 subtype of medulloblastoma experience poor outcomes, with nearly 50% mortality despite intensive treatment regimens. Thus, new treatment options are desperately needed. While prior efforts have studied the ~20,000 known protein-coding genes in medulloblastoma, I have investigated >2,000 non- canonical proteins that were previously excluded. I have discovered that MYC-driven, Group 3 medulloblastoma cells are dependent on an upstream open reading frame (uORF) encoded within the ASNSD1 5’ untranslated region. Perturbation of this uORF impacted the MYC cellular program, and it bound to the prefoldin complex, which is critical for gene regulation. These findings provide a rationale to study ASNSD1 uORF as an oncogenic driver in medulloblastoma and suggest that non-canonical proteins are a fertile territory for cancer discovery. To advance ASNSD1 uORF as a potential therapeutic target, this proposal will pursue two specific aims in the context of Group 3 medulloblastoma: (1) to validate ASNSD1 uORF in advanced cell line and mouse models of medulloblastoma and (2) to confirm the role of the ASNSD1-prefoldin complex interaction in medulloblastoma. I am an Instructor in Pediatric Neuro-oncology with at least 80% protected time for research, who is committed to uncovering medulloblastoma disease mechanisms to advance patient care. My career goal is to become an independent physician-scientist with research focused on novel medulloblastoma therapeutic targets. The purpose of this career development award is to enable me to gain specific research training in medulloblastoma mouse model systems, proteomics techniques and computational analysis. I seek to use these research skills to advance my work studying non-canonical proteins as novel medulloblastoma vulnerability genes. I have chosen an outstanding mentorship team of Drs. Todd Golub and Pratiti Bandopadhayay for this proposal. Dr. Golub is an authority on the discovery of therapeutic targets and brings over 20 years of experience in mentoring K08-level physician scientists. I have selected Dr. Bandopadhayay as a co-mentor because she is an innovator in medulloblastoma and deep knowledge of medulloblastoma model systems. My advisory committee includes experts reflecting key areas of my training plan: Drs. Steve Gygi (proteomics), Scott Pomeroy (medulloblastoma), Ernest Fraenkel (computational biology) and Kim Stegmaier (pediatric genomics). Both my mentor, co-mentor, and advisory committee are committed to my research training, career development and growth into an independent physician-scientist at the conclusion of this award. I will train at the Dana-Farber Cancer Institute and the Broad Institute, which are both outstanding institutions with unique research opportunities. This training environment provides numerous opportunities for me to benefit from didactic coursework relevant to this award, as well as participate in world-class research conferences. With the mentored research and career development offered through this K08 award, I will be ideally suited to establish my independent career as a physician-scientist in pediatric neuro-oncology.

项目摘要/摘要 患有髓母细胞瘤3组亚型的儿童的结果差，死亡率近50％ 尽管有密集的治疗方案。那是迫切需要新的治疗选择。在事先努力的同时 已经研究了髓母细胞瘤中约有20,000个已知的蛋白质编码基因，我研究了> 2,000个非 - 以前被排除的规范蛋白质。我发现MYC驱动的3组髓母细胞瘤 单元格取决于在ASNSD1 5'未翻译中编码的上游开放式阅读框架（UORF） 地区。该UORF的扰动影响了MYC细胞程序，并与preoldin复合物结合， 这对于基因调节至关重要。这些发现为研究ASNSD1 UORF作为致癌性提供了理由 髓母细胞瘤的驱动器，并暗示非典型蛋白是发现癌症的肥沃领域。到 提出ASNSD1 UORF作为潜在的治疗目标，该提案将在 第3组髓母细胞瘤的上下文：（1）在高级细胞系中验证ASNSD1 UORF和鼠标模型 髓母细胞瘤和（2）确认在髓母细胞瘤中ASNSD1-Preoldin复合物相互作用的作用。 是小儿神经肿瘤学的讲师，至少有80％的研究时间进行研究，他们致力于 揭示髓母细胞瘤疾病机制以改善患者护理。我的职业目标是成为一个 独立的物理科学家与研究有关新型髓母细胞瘤治疗靶标的研究。这 这个职业发展奖的目的是使我能够在髓母细胞瘤中获得特定的研究培训 小鼠模型系统，蛋白质组学技术和计算分析。我寻求使用这些研究技能 为了推动我研究非典型蛋白作为新型髓母细胞瘤脆弱性基因的工作。我有 选择一个杰出的DRS心态。 Todd Golub和Pratiti Bandopadhayay为此提案。博士 Golub是发现治疗靶标的权威，并带来了20多年的心理经验 K08级的物理科学家。我选择了Bandopadhayay博士作为联合主管，因为她是创新者 在髓母细胞瘤和髓母细胞瘤模型系统的深刻知识中。我的咨询委员会包括 专家反映我的培训计划的关键领域：Drs。 Steve Gygi（蛋白质组学），Scott Pomeroy（髓母细胞瘤）， Ernest Fraenkel（计算生物学）和Kim Stegmaier（小儿基因组学）。我的精神，同事， 和咨询委员会致力于我的研究培训，职业发展和成长为 独立的身体科学家在本奖项结束时。我将在Dana-Farber癌症研究所训练 以及广泛的研究所，它们都是具有独特研究机会的杰出机构。这个培训 环境为我提供了许多机会，可以从与该奖项相关的教学课程中受益， 以及参加世界一流的研究会议。随着指导的研究和职业发展 通过这个K08奖提供，我将非常适合建立我作为身体科学家的独立职业 在小儿神经肿瘤学中。