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.

摘要 在过去的十年里，我们表征和研究了各种tRNA衍生的性质 小RNA(TsRNAs)。近年来，我们将重点放在一类通常提到的 AS 3‘tsRNAs(源自成熟tRNAs的3’端)，因为它们是最差的 被研究但似乎在组织再生(如肝脏再生)中发挥作用 包括癌症在内的过度增殖状态。在这里，我们计划建立目标定位的潜力 用于治疗目的的3‘tsRNA。最近，我们确定了一种特定的RNA，即 22nt CAG-亮氨酸3‘tsRNA，当加入反义时下调 快速分裂但不是静止的细胞中的寡核苷酸抑制核糖体的生物发生。损失 这种特定的tsRNA限制了至少一个核糖体的翻译(在伸长阶段) 蛋白质信使核糖核酸这会导致rRNA加工受阻，并导致细胞快速凋亡。在……里面 相比之下，添加3‘tsRNA模拟物可以促进细胞增殖并补充 细胞中的核糖体生物发生缺陷。我们建议进一步鉴定其他3‘tsRNA-mRNA 相互作用，建立它们的生物和分子功能，发展基因治疗 和寡核苷酸反义递送技术，以追求治疗潜力 在动物体内操纵3‘tsRNA。虽然tsRNAs在许多组织中都有表达，但我们 将把这些研究的重点放在肝脏，包括肝癌。这项工作将提供新的 健康中3‘tsRNA在基因调控和细胞内稳态中的作用 和疾病状态，以及通过建议的 临床前人类异种移植小鼠动物模型。在经修订的申请书内，我们 删除了所有与筛选改进的LNPs相关的研究，这些研究在之前的 评审员建议的目标3。