3' tsRNAs: biologic function and pre-clinical targeting for treating human disease

3 tsRNA：治疗人类疾病的生物学功能和临床前靶向

• 批准号: 10735190
• 负责人: Mark A Kay
• 金额: $ 54.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-08 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735190
• 关键词: Amendment; Animal Model; Animals; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Apoptosis; Biogenesis; Bioinformatics; Biological; Biological Models; Biological Process; Cell Proliferation; Cells; Complement; Data; Defect; Disease; Dose; Effectiveness; Excision; Gene Expression Regulation; Gene Transfer; Goals; Health; Homeostasis; Human; Induction of Apoptosis; Journals; Learning; Left; Leucine; Liver; Liver Regeneration; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Medicine; Messenger RNA; Modeling; Molecular; Mus; Nature; New England; Nomenclature; Oligonucleotides; Paper; Pathologic; Patients; Phenotype; Porifera; Primary carcinoma of the liver cells; Production; Property; Protein Biosynthesis; Proteins; RNA; RNA, Ribosomal, 18S; Recombinant adeno-associated virus (rAAV); Ribosomal Proteins; Ribosomal RNA; Ribosomes; Role; Small RNA; Technology; Therapeutic; Time; Tissues; Transfer RNA; Translations; Tumor-Derived; Untranslated RNA; Work; Xenograft procedure; antitumor effect; gene therapy; guided inquiry; human disease; improved; insight; molecular sequence database; mouse model; pre-clinical; regenerative; screening; tissue regeneration; tumor; vector

ABSTRACT Over the last decade we characterized and studied the properties of various tRNA derived small RNAs (tsRNAs). In recent years, we have focused on one class commonly referred to as 3’tsRNAs (derived from the 3’end of mature tRNAs) because they are the least well studied but appear to play a role in tissue regeneration (e.g., liver regeneration) and hyperproliferative states including cancer. Here we plan to establish the potential of targeting the 3’tsRNAs for therapeutic purposes. Recently, we established that one specific RNA, the 22nt CAG-Leucine 3’tsRNA, which when down regulated by the addition of antisense oligonucleotides in rapidly dividing but not quiescent cells inhibit ribosome biogenesis. Loss of this specific tsRNA limits the translation (at the elongation step) of at least one ribosomal protein mRNA. This results in a block in rRNA processing and rapid cellular apoptosis. In contrast, the addition of a 3’tsRNA mimic increases cellular proliferation and can complement the ribosome biogenesis defect in cells. We propose to further identify other 3’tsRNA-mRNA interactions and establish their biologic and molecular function and develop gene therapy and oligonucleotide antisense delivery technologies to pursue the therapeutic potential of manipulating 3’tsRNAs in animals. Although the tsRNAs are expressed in many tissues, we will focus these studies on the liver including liver cancer. This work will provide new information related to 3’tsRNA function in gene regulation and cellular homeostasis in health and disease states, as well as establish their potential therapeutic value by the proposed preclinical human xenotransplant murine animal models. In the amended application, we removed all the studies related to screening for improved LNPs outlined in previous specific aim 3 as suggested by the reviewers.

抽象的 在过去的十年中，我们表征并研究了各种 tRNA 衍生的特性 近年来，我们主要关注一类通常提到的小RNA（tsRNA）。 为 3'tsRNA（源自成熟 tRNA 的 3' 端），因为它们的状态最差 研究过但似乎在组织再生（例如肝再生）中发挥作用 在此，我们计划确定靶向的潜力。 最近，我们确定了一种特定的 RNA，即用于治疗目的的 3’tsRNA。 22nt CAG-亮氨酸 3’tsRNA，当添加反义时下调 快速分裂但静止细胞中的寡核苷酸抑制核糖体生物发生。 这种特定的 tsRNA 限制了至少一种核糖体的翻译（在延伸步骤） 这会导致 rRNA 加工受阻并导致细胞快速凋亡。 相比之下，添加 3'tsRNA 模拟物会增加细胞增殖并可以补充 我们建议进一步鉴定其他 3'tsRNA-mRNA。 相互作用并建立其生物学和分子功能并开发基因疗法 和寡核苷酸反义递送技术，以追求其治疗潜力 虽然 tsRNA 在许多组织中表达，但我们在动物中操纵 3’tsRNA。 将这些研究重点放在肝脏（包括肝癌）上，这项工作将提供新的内容。 与 3’tsRNA 在健康基因调控和细胞稳态中的功能相关的信息 和疾病状态，并通过提议的方法确定其潜在的治疗价值 在修订后的申请中，我们对临床前人类异种移植小鼠动物模型进行了研究。 删除了先前特定中概述的与筛选改良 LNP 相关的所有研究 审稿人建议的目标 3。