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 患有第3组亚型髓母细胞瘤的儿童预后不佳，死亡率接近50% 尽管有密集的治疗方案。因此，迫切需要新的治疗方案。虽然之前的努力 我研究了髓母细胞瘤中已知的~20,000个蛋白质编码基因，我研究了&gt；2,000个非 以前被排除在外的典型蛋白质。我发现由MYC驱动的第3组髓母细胞瘤 细胞依赖于在ASNSD1 5‘未翻译内编码的上游开放阅读框(uORF 区域。该uORF的干扰影响了MYC细胞程序，并与前折叠蛋白复合体结合， 这对基因调控至关重要。这些发现为将ASNSD1 uORF作为致癌因素进行研究提供了理论基础 髓母细胞瘤的驱动因素，并表明非规范蛋白是发现癌症的肥沃领域。至 高级ASNSD1 uORF作为潜在的治疗靶点，这项建议将在 第3组髓母细胞瘤的背景：(1)验证ASNSD1 uORF在高级细胞系和小鼠模型中的有效性 和(2)证实ASNSD1-前折叠蛋白复合体相互作用在髓母细胞瘤中的作用。我 我是一名儿科神经肿瘤学讲师，至少有80%的受保护时间用于研究，我致力于 揭示髓母细胞瘤的发病机制，以促进患者的护理。我的职业目标是成为一名 独立内科医生兼科学家，专注于新的髓母细胞瘤治疗靶点的研究。这个 这个职业发展奖的目的是使我能够在髓母细胞瘤方面获得专门的研究培训 小鼠模型系统、蛋白质组学技术和计算分析。我试图利用这些研究技能 为了推进我的工作，研究非典型蛋白作为新的髓母细胞瘤易感基因。我有过 选择了托德·戈卢布博士和Patiti Bandopadhayay博士的优秀指导团队来完成这项提议。Dr。 戈卢布是发现治疗靶点的权威，在指导方面拥有20多年的经验。 K08级内科科学家。我选择Bandopadhayay博士作为共同导师，因为她是一位创新者 对髓母细胞瘤和髓母细胞瘤模型系统有深入的了解。我的顾问委员会包括 反映我培训计划关键领域的专家：Steve Gygi博士(蛋白质组学)，Scott Pomeroy博士(髓母细胞瘤)， 欧内斯特·弗拉恩克尔(计算生物学)和金·斯泰格迈尔(儿科基因组学)。我的导师，共同导师， 和咨询委员会都致力于将我的研究培训、职业发展和成长成长为 独立内科医生-科学家在该奖项结束时。我将在达纳-法伯癌症研究所接受培训 和远大研究所，这两个都是拥有独特研究机会的杰出机构。这次培训 环境为我提供了许多机会，让我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。有指导的研究和职业发展 通过K08奖项，我将非常适合建立我的独立职业生涯，作为一名内科科学家 儿科神经肿瘤学。