55 studying the role of stem cells in the development of brain tumors and their use as a vehicle in gene therapy. • The bi-directional interaction between the nervous and immune systems and the role of this interaction in the function of neuronal and glial cells during physiological andpathological conditions. Abstract Abstract Topic 1 Cancer stem cells from brain tumors GBMs contain a small subpopulation of cancer cells called glioma stem cells (GSCs) that are characterized by the ability to selfrenew, exhibit multi-lineage differentiation potential and the generation of xenografts that recapitulate the parental tumor. GSCs are resistant to conventional therapies as compared with differentiated tumor cells, and therefore remain at the tumor site following resection, which eventually leads to tumor recurrence. Therefore, delineating the cellular and molecular mechanisms that control the stemness and functions of GSCs is essential for identifying therapeutic approaches to selectively target GSCs. We have been demonstrated the role of autophagy in determining the radiation resistance of GSCs and identified specific signaling pathways such as the miR-137RTVP-1-CXCR4 pathway and the RasGEF, RasGRP3 in controlling the stemness and migration of GSCs. In addition to glioma, we have also established cancer stem cells from meningioma and brain metastases from lung and breast tumors. For all these tumors we currently have neurospheres, organoids and patient derived xenografts (PDX). WE are employing these models for studying the role of novel non-coding RNAs in the biology of these cells and in their cross-interaction with microglia via exosomal delivery. Abstract Topic 2 Exosomes in intercellular communication and drug delivery and therapeutics Exosomes are small vesicles released by all cells in the body and play major roles in intercellular interaction. Exosomes can be isolated from serum and plasma (in addition to almost every body’s fluid) and serve as important source for circulating biomarkers. Exosomes carry a very heterogeneous cargo that in many cases reflects the nature and status of the secreting cells. Therefore, exosomes can be employed to analyze disease status is a tissue-dependent manner and response of various cells to different therapies. In addition, exosomes can be employed to deliver different therapeutics such as proteins, RNA molecules and oncolytic viruses. We have developed novel approaches to track exosomes and their cargo in vitro and in vivo and exosomes targeted to specific cells and tissues and demonstrated therapeutic impact in a number of pre-clinical models. Abstract Topic 3 Human in vitro models of neurological disorders. We have generated various immortalized human cells including neural stem cells (NSCs), astrocytes, microglia, oligodendrocytes, and neurons that maintain the phenotypes and functions of the original cells. Using CRISPR/ Cas9 we can generate various models of neurological diseases and study disease mechanisms and neuron-glia cell interactions. Moreover, we have developed an array of reporters that allow us to analyze cell differentiation, fate and signaling pathways in pathological conditions and in response to various treatments. Abstract Topic 4 Collaboration with BioIncept LLC We are actively collaborating with BioIncept on the protective effects of a peptide sPIF from acute radiation syndrome (ARS) and in other studies related to the effects of sPIF in neurological disorders and Duchenne muscular dystrophy. In addition, we have been studying the effects of sPIF on glioma cells and cancer stem cells derived from brain metastases. Publications 2021 and 2022 · Donald Penning, Simona Cazacu, Raphael Nizar, Hodaya Goldstein, Gila Kazimirsky, Stephen Brown, Lisa Rogers, Chaya Brodie. “BSCI-05 REPURPOSING PROPOFOL FOR THE TREATMENT OF BRAIN METASTASES”. Neuro-oncology Advances, 2022. · S Kivity, H Kravitz, C Cohen, D Margoulis, M Amar, G Kazimirsky, D Ozeri, A Dori, C Brodie. “POS0468 EXTRACELLULAR VESICLES FROM SERUM OF MYOSITIS PATIENTS AS CIRCULATING BIOMARKERS AND DISEASE MEDIATORS”. Annals of the Rheumatic Diseases 81 (Suppl 1), 488-488, 2022. · Shlomit Brodie, Hae Kyung Lee, Wei Jiang, Simona Cazacu, Cunli Xiang, Laila M Poisson, Indrani Datta, Steve Kalkanis, Doron Ginsberg, Chaya Brodie. “Correction: The novel long non-coding RNA TALNEC2, regulates tumor cell growth and the stemness and radiation response of glioma stem cells”. Oncotarget, 2021. · Donald H Penning, Simona Cazacu, Aharon Brodie, Vesna Jevtovic-Todorovic, Steve N Kalkanis, Michael Lewis, Chaya Brodie. “Neuron-Glia Crosstalk Plays a Major Role in the Neurotoxic Effects of Ketamine via Extracellular Vesicles”. Frontiers in Cell and Developmental Biology, 2021. · Indrani Datta, Houtan Noushmehr, Chaya Brodie, Laila M Poisson. “Expression and regulatory roles of lncRNAs in G-CIMPlow vs G-CIMP-high Glioma: an insilico analysis”. Journal of translational medicine, 2021. · Irene Unterman, Idit Bloch, Simona Cazacu, Gila Kazimirsky, Bruria Ben-Zeev, Benjamin P Berman, Chaya Brodie, Yuval Tabach. “Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome”. Elife, 2021. · Hadar Peeri, Nurit Shalev, Ajjampura C Vinayaka, Rephael Nizar, Gila Kazimirsky, Dvora Namdar, Seegehalli M Anil, Eduard Belausov, Chaya Brodie, Hinanit Koltai. “Specific Compositions of Cannabis sativa Compounds Have Cytotoxic Activity and Inhibit Motility and Colony Formation of Human Glioblastoma Cells In Vitro”. Cancers, 2021.
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