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

Stanford University, Stanford CA

Investigators

Abstract

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.