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.

项目概要/摘要 患有第 3 组髓母细胞瘤亚型的儿童预后较差，死亡率接近 50% 尽管强化治疗方案。因此，迫切需要新的治疗选择。虽然之前的努力 研究了髓母细胞瘤中约 20,000 个已知的蛋白质编码基因，我研究了超过 2,000 个非 之前被排除的典型蛋白质。我发现 MYC 驱动的第 3 组髓母细胞瘤 细胞依赖于 ASNSD1 5' 未翻译内编码的上游开放阅读框 (uORF) 地区。这个 uORF 的扰动影响了 MYC 细胞程序，并且它与前折叠蛋白复合物结合， 这对于基因调控至关重要。这些发现为研究 ASNSD1 uORF 作为致癌物质提供了理论依据 髓母细胞瘤的驱动因素，并表明非典型蛋白质是癌症发现的沃土。到 推进 ASNSD1 uORF 作为潜在的治疗靶点，该提案将追求两个具体目标 第 3 组髓母细胞瘤的背景：(1) 在高级细胞系和小鼠模型中验证 ASNSD1 uORF (2) 确认 ASNSD1-前折叠蛋白复合物相互作用在髓母细胞瘤中的作用。我 是一名儿科神经肿瘤学讲师，拥有至少 80% 的受保护时间用于研究，致力于 揭示髓母细胞瘤疾病机制以促进患者护理。我的职业目标是成为 独立医师科学家，专注于新型髓母细胞瘤治疗靶点的研究。这 该职业发展奖的目的是使我能够获得髓母细胞瘤方面的具体研究培训 小鼠模型系统、蛋白质组学技术和计算分析。我寻求利用这些研究技能 推进我将非典型蛋白质作为新型髓母细胞瘤易感基因的研究工作。我有 选择了优秀的博士导师团队。 Todd Golub 和 Pratiti Bandopadhayay 对此提案的贡献。博士。 Golub 是发现治疗靶点方面的权威，并拥有 20 多年的指导经验 K08级医师科学家。我选择 Bandopadhayay 博士作为共同导师，因为她是一位创新者 髓母细胞瘤和髓母细胞瘤模型系统的深入了解。我的顾问委员会包括 反映我的培训计划关键领域的专家：博士。 Steve Gygi（蛋白质组学）、Scott Pomeroy（髓母细胞瘤）、 Ernest Fraenkel（计算生物学）和 Kim Stegmaier（儿科基因组学）。我的导师、共同导师， 和顾问委员会致力于我的研究培训、职业发展和成长为一名 独立医师科学家在该奖项结束时。我将在丹娜法伯癌症研究所接受培训 和布罗德研究所，它们都是拥有独特研究机会的杰出机构。本次培训 环境为我提供了许多机会从与该奖项相关的教学课程中受益， 以及参加世界级的研究会议。通过指导研究和职业发展 通过这个 K08 奖项，我将非常适合建立我作为一名医师科学家的独立职业生涯 在儿科神经肿瘤学。