Small non-coding RNAs including microRNAs (miRNAs), short interfering RNAs (siRNAs) or Piwi interacting RNAs (piRNAs) have been discovered recently and extensive research revealed that such RNAs function as key-regulators of gene expression. Small non-coding RNAs cooperate with members of the Argonaute (Ago) protein family to regulate gene expression at the level of transcription, mRNA stability or translation. While small RNAs serve as sequence-specific guides, Ago proteins constitute the mediators of gene silencing processes. In order to identify functional classes of small non-coding RNAs, it is important to analyze interactions with members of the Ago protein family. We propose to isolate and clone Ago-associated small RNAs. Processing products of small nucleolar RNAs (snoRNAs) can give rise to functional small RNAs and it is very likely that other non-coding RNAs including tRNAs or rRNAs produce functional small RNAs with so far unrecognized cellular functions. In the second part of the proposal we plan to investigate the role of miRNAs in disease. In the cancer field, the cancer stem cell hypothesis suggests the existence of tumor stem cells that are important for tumor maintenance. Such stem cells are difficult to target and might be the cause of tumor re-appearance after therapy. Since glioblastoma is a fatal tumor and tumor stem cells can be isolated we will analyze miRNA expression in glioblastoma stem cells. Indeed, a first cloning approach identified several tumor stem cell specific miRNAs. In the proposed project we plan to analyze the biological function of such glioblastoma stem cell-specific miRNAs. We hope that our work not only contributes to a better understanding of the cancer stem cell hypothesis but will also depict new ways for cancer therapy.
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