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: 10848880
• 负责人: John Prensner
• 金额: $ 23.21万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10848880
• 关键词: Deciphering; non; canonical; translation; risk

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.

项目总结/文摘

项目成果

Shining a light on the dark proteome: Non-canonical open reading frames and their encoded miniproteins as a new frontier in cancer biology.

• DOI: 10.1002/pro.4708
• 发表时间: 2023-08
• 期刊: Protein science : a publication of the Protein Society

Deep learning to decode sites of RNA translation in normal and cancerous tissues.

深度学习解码正常组织和癌组织中的 RNA 翻译位点。

• DOI: 10.1101/2024.03.21.586110
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Clauwaert,Jim;McVey,Zahra;Gupta,Ramneek;Yannuzzi,Ian;Menschaert,Gerben;Prensner,JohnR
• 通讯作者: Prensner,JohnR