Project 4-Monika Rak

摘要：神经胶质肿瘤是美国最常见的恶性脑肿瘤

Abstract: Glial tumors are the most commonly occurring malignant brain tumor in the United States, among which approximately 20% are glioblastomas, which are the most aggressive and practically incurable. Drug resistance is often associated with the existence of a discrete population of cells, which demonstrate a stem-like phenotype. In glioblastoma, these cells are known as glioma initialing cells (GICs), and their expansion is often linked with tumor recurrence. Human endogenous retroviral sequences (HERVs) are mobile elements of the viral origin that comprise nearly 8% of the human genome. In HERVs, like in all retroviruses, genes encoding viral proteins are flanked by long terminal repeats (LTRs). Serving as promoters, LTRs are particularly enriched in binding motifs for transcription factors. Importantly, recent studies show that HERV transcripts are upregulated during early human development, including CNS development, when cellular pluripotency and stem-like phenotype predominate. Reactivation of HERV loci are also associated with different tumors, however, the cause and effect relationship between HERVs and cancer have not been established. Therefore, the effect/s of HERVs on the development and maintenance of stem-like phenotype in glioblastoma tumors, and the associated drug resistance, require further investigation. We hypothesize that aberrant expression of HERVs found in glioblastoma clinical samples contributes to the enhanced glioblastoma stem-like phenotype and associated drug resistance. We will test this general hypothesis by executing our experimental plan that consists of two independent but logically connected Specific Aims: In Aim 1 we will determine HERV transcript levels in glial tumors, and analyze if high HERV transcription correlates with: a) specific glioblastoma subtype: pro-neural (17 months survival), classical (14 months survival), mesenchymal (11.5 months survival), as compared to low-grade gliomas (90% curable); b) glioblastoma stem-specific transcription pattern. In Aim 2 we will analyze effects of inducible Crisp/Cas-based -upregulation and -downregulation of HERV transcripts on stem-like phenotype and malignant growth of low grade gliomas and glioblastomas, respectively. The long- term objective is to establish the role of HERV transcripts in establishing highly malignant phenotype of glioblastoma, and to use this knowledge in the development of new therapeutic strategies against these terminal brain neoplasms.