Investigate the Role of Rgss and P2y Receptors in Brain Tumor Progression and Neural Development

Signaling pathways regulating neural development can also play a role in brain tumorigenesis. Studying the molecular regulation of these signaling pathways can provide insights regarding nervous system development and lead to potential therapeutic strategies for the treatment of brain tumors. The aim of this study is to identify a novel regulatory mechanism underlying both neural development and brain tumorigenesis. We will focus on regulator of G-protein signaling (RGS) and purinergic P2Y receptor (P2RY) proteins. Both of these protein families are mediators of G-protein signaling; however, the interaction between P2RY and RGS remains unclear, and the role of these proteins in either the developing nervous system or brain tumor progression has not been extensively studied. We previously determined that many RGS/rgs and P2RY/p2ry genes are expressed in both the developing nervous system and in brain tumor cells. We demonstrate that, in SH-SY5Y cells neuroblastoma cell line, activation of P2RY1 upregulates AKT signaling and induces tumor cell growth; furthermore, this effect was inhibited by RGS2. On the contrary, in the zebrafish nervous system, P2ry1 induced Mapkl and neural cell proliferation, which was inhibited by Rgs2. Based on these results, we hypothesized that P2RY-RGS-AKT/MAPK can regulate neural development and tumor progression in a cell-type specific manner. In this study, we will expand our observations to study the role of P2RY and RGS proteins and their underlying mechanisms in neural cells. We will use gain- and loss-of-function strategies to analyze their effects on cell progression and identify specific Ga proteins involved in this P2RY-RGS regulation. In addition, the potential downstream effectors involved in P2RY-RGS-Ga signaling, including adenylate cyclase, PLCP, AKT, and MAPK, will be examined. This study will be performed using two model systems, brain tumor cell lines and zebrafish embryos; models with several advantages that will complement and advance our studies involving P2RY-RGS signaling functions. Moreover, the transplantation of tumor cell lines into zebrafish will improve our understanding of tumor cell progression in v/vo. This study will delineate a novel signaling pathway, and discover different molecular combinations involved in P2RY-RGS signaling that can regulate brain tumor progression and the neural development of zebrafish in various aspects. This study will help uncover the different roles of P2RY-RGS-mediated regulatory mechanisms in brain tumor progression and neural development, to improve our understanding of neurodevelopmental disorders, leading to the identification of therapeutic compounds for brain tumors. Our laboratory has an extensive track record of research productivity using zebrafish models to study P2RY receptors, RGS proteins, and AKT signaling. To strengthen brain tumorigenesis studies, we will collaborate with two attending physicians, Dr. Tu-Hsueh Yeh (Department of Neurology) and Dr. Yin-Cheng Huang (Department of Neurosurgery) in Chang Gung Memorial Hospital, who are experts in brain cancer.

Project ID:PC10507-0245
External Project ID:MOST105-2320-B182-021