ד"ר מרים הורביץ פריד

1997-1999: B.Sc., Biology (Cellular and molecular biology)  , Bar-Ilan University. 

                          Graduated with High Honors   

                         2000-2002: M.Sc., Biotechnology, Bar-Ilan University.
                        Title: "Insulin-induced glucose uptake in L8 skeletal muscle: importance of PKC     

                        delta "

                        Supervisor: Prof. Sanford Sampson.                         

                        Graduated with High Honors   

                        2003- 2007: Ph.D, Biology, Bar-Ilan University
                         Title: "Expression regulation of isoenzyme from PKC family by insulin in skeletal  

                         muscle."

                        Supervisor: Prof. Sanford   Sampson.           

                                     2017-present:  Researcher in  laboratory  of Immune Gene Editing, headed by Dr Adi  

                                     Barzel . School of biochemistry and molecular biology, faculty of life science,                 

                                               Tel-Aviv university.

           2007-2008:  Research fellowship in  lab of cellular biology headed by Prof. Sanford  

            Sampson , Bar-Ilan university.

            2008-2009 : review of biology and chemistry patent files, T. Colb office

            2008-2017: lab manager in Laboratory of Tumor Immunology and

              Immunotherapy headed by Prof. Cyrill Cohen. Bar-Ilan university

           Responsibilities: As a laboratory manager, I was involved in all aspects of the

             scientific research, including guiding graduate students, take part  in  writing articles 

            and grants,   and also responsibility of  the  technical aspects of lab management.         

2003-2007 : “President’s Scholarships for Outstanding Doctoral Students” program at Bar-Ilan University.

2005-2006:  Scholarship for" encourage excellence in research" .  faculty of life Science, Bar-Ilan university.

1999: Scholarship for excellence in studies . faculty of life Science, Bar-Ilan university.

Summary of Past Research and Development Activities :

 In the past my research focused on the engineering of the immune response against  cancer by introducing genes of interest into T-lymphocytes.

 The immune response against tumor cells has been proven crucial to the elimination of cancer. Several factors such as the tumor micro-environment or tumor-escape mechanisms are interfering the immune response of the cytotoxic CD8⁺T-lymphocytes in the body.  Therefore ,the research studying the dynamics of TCR-gene transfer in human cells and improving this process by combining molecular and structural biology as well as gene therapy approaches.

In the lab, the recherché   tried to find a new ways to improve the anti-tumor response of lymphocytes by endowing them with other immune molecules such as co-activators molecules and that would enhance their biological activity and expansion , and chemokines that help  the CD8⁺T-lymphocytes to migrate more effectively to the tummor  .  (Was done in the lab of Cyrill Cohen, Bar Ilan university)

Summary of Current Research and Development Activities:

Engineering T cells for Immunotherapy using VDJ targeting

T cell engineering for immunotherapy currently relies on cumbersome ex vivo

manipulations, performed in specialized centres only. Conversely, Adeno associated vectors (AAV) allow lymphocyte transduction both in vivo and ex vivo, without activation. However, AAV vectors are seldom used for lymphocyte engineering as they rarely integrate for stable expression in dividing cells. The current study  propose a novel immunotherapy approach targeting AAV-delivered immune genes into the genome using V(D)J recombination in developing lymphocytes. In particular, we target chimeric antigen receptor (CAR) or T cell receptor (TCR) genes into loci coding TCR chains and

target antibody (Ab) genes into loci coding Ab chains. A promoterless receptor/Ab gene flanked by recognition signal sequences (RSS) will be inserted into the endogenous locus by the recombination activating gene (RAG) complex during V(D)J recombination. Only developing lymphocytes, expressing RAG, incorporate the receptor/Ab gene, which thus be expressed in potent naïve cells, which will selectively expand following antigen-induced activation. Targeted T cells will express only the desired receptors, due to allelic exclusion.

(Was done in the lab of Adi Barzel, Tel-Aviv university)

Future Directions for Research and Development.

We will target ex vivo differentiating lymphocytes and demonstrate

efficacy upon implantation in models of cancer and autoimmune disease. VDJ targeting may allow safe, efficient and scalable engineering of T cells, both in vivo and ex vivo.

We will use VDJ targeting rates in lymphocytes differentiated from

pluripotent cell sources: human UCB HSCs or human BM HSCs, differentiate them, using feeder cells and cytokines, to mature T cells ex-vivo. The cells will be transduced with our AAV vectors at different stages of the ex vivo differentiation. Subsequently, the anti-tumor activity of the transduced cells assessed by in-vitro killing assay and in xenograft model.

                          To engineer inducible B cells:  We will target the integration of a cassette separately

                       coding for a secreted Ab and a BCR targeting different antigens. The Ab is directed

                         against a disease associated antigen (often autoantigen) and the BCR is directed against

                         a foreign inducer. The B cell will differentiate to Ab-secreting plasma cells only upon

                      administration of the foreign inducer 

( in the lab of Adi Barzel, Tel-Aviv university)

1. Horovitz-Fried M., Brand C., Cipok M., Bak A., InbarA., Patel N., Cooper D. R. and Sampson R. S. Insulin rapidly upregulates protein kinase C delta gene expression. Cell Signaling Feb 2006;18(2):183-93. (IF: 4.305, Citations: 17, Q1)

1. Horovitz-Fried M., Jacob A. , Cooper D. R. and Sampson R. S., Activity of the Nuclear Transcrition Factor SP-1 by Insulin rapidly Increases the Expression of Protein Kinase C Delta in Skeletal Muscle. Cell Signaling Mar 2007;19(3):556-62. (IF: 4.305, Citations: 20,Q1)

1. Horovitz-Fried M., and Sampson R. S. PKC  Involved in Insulin-Induced PKC Expression: Importance of SP-1 and NFB Transcription Factors. BBRC 352 (2007) 78-83. (IF: 2.648, Citations: 19,Q1)

1. Horovitz-Fried M., Brutman-Barazani T.,Kesten D and Sampson R. S. Insulin Increases Nuclear PKC in L6 Skeletal Muscle. Endocrinology. Apr 2008;149(4):1718-27. ( IF:4.276, Citation  15, Q1)

5. Jacob AI, Horovitz-Fried M, Aga-Mizrachi S, Brutman-Barazani T, Okhrimenko H, Zick Y, Brodie C, Sampson SR. The regulatory domain of protein kinase C delta positively regulates insulin receptor signaling. J Mol Endocrinol. Mar 2010;44(3):155-69. (IF: 3.081, Citations: 13,Q1)
   
   

1. Bialer G, Horovitz-Fried M, Ya'acobi S, Morgan RA, Cohen CJ. Selected murine residues    endow human TCR with enhanced tumor recognition. J Immunol. Jun 2010 1;184(11):6232-41. ( IF:5.185,  Citation:69, Q1)

1. S.R. Sampson., E.Bucris., M. Horovitz-Fried, A. Parnas, S. Kahana1, G. Abitbol M. Chetboun, T. Rosenzweig, C.Brodie and S. Frankel. Insulin Increases Apoptosis in Pancreatic Beta (β) Cells. Apoptosis. 2010 Oct;15(10):1165-76. ( IF:3.967,  Citation:24,Q1)

8. Brand C, Horovitz-Fried M, Inbar A, Tamar-Brutman-Barazani, Brodie C, Sampson SR.. Insulin stimulation of PKCdelta triggers its rapid degradation via the ubiquitin-proteasome pathway. Biochim Biophys Acta. 2010 Nov;1803(11):1265-75. (IF: 3.062, Citations: 13,Q1)

1. Brutman-Barazani T, Horovitz-Fried M, Aga-Mizrachi S, Brand C, Brodie C, Rosa J, Sampson SR .Protein kinase Cδ but not PKCα is involved in insulin-induced glucose metabolism in hepatocytes. J Cell Biochem. 2012 Jun;113(6):2064-76. (IF: 3.062, Citations: 14,Q1)

1. Haga-Friedman A, Horovitz-Fried M, Cohen CJ. Incorporation of Transmembrane Hydrophobic Mutations in the TCR Enhance Its Surface Expression and T Cell Functional Avidity.    J Immunol. 2012 Jun 1;188(11):5538-46. ( IF: 5.185, Citation:22,Q1)

1. Daniel-Meshulam I, Horovitz-Fried M, Cohen CJ. Enhanced anti-tumor activity mediated by human 4-1BB-engineered T-cells. Int J Cancer. 2013 Dec 15;133(12):2903-13. ( IF:5.531  Citation:15, Q1)

1. Ankri C, Shamalov K, Horovitz-Fried M, Mauer S, Cohen CJ. Human T Cells Engineered To Express a Programmed Death 1/28 Costimulatory Retargeting Molecule Display Enhanced Antitumor Activity. J Immunol. 2013 Oct 15;191(8):4121-9. ( IF: 5.185, Citation:39,Q1)

13.  Tal Y, Yaakobi S, Horovitz-Fried M, Safyon E, Rosental B, Porgador A, Cohen CJ. An NCR1-based chimeric receptor endows T-cells with multiple anti-tumor specificities. Oncotarget. 2014 Nov 15;5(21):10949-58. ( IF: 6.359, Citation:8, Q1)

1. Rinat Meir, Katerina Shamalov, Oshra Betzer, Menachem Motiei, Miryam Horovitz-Fried, Ronen Yehuda, Aron Popovtzer, Rachela Popovtzer, and Cyrille J. Cohen Nanomedicine for Cancer Immunotherapy: Tracking Cancer-Specific T‑Cells in Vivo with Gold Nanoparticles and CT Imaging.  2015 Jun 11 ACS Nano. ( IF:13.709,  Citation:11,Q1)

1. Cyrille J. Cohen, Jared J. Gartner, Miryam Horovitz-Fried, Katerina Shamalov, Kasia Trebska-McGowan, Valery. Bliskovsky, Maria R. Parkhurst, Chen Ankri,1 Todd. D. Prickett, Jessica S. Crystal, Yong F. Li, Mona El-Gamil, Steven A. Rosenberg, and Paul F. Robbins.  Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes. The Journal of Clinical Investigation.  2015 Oct 1;125(10):3981-91. ( IF: 13.25,  Citation:67,Q1)

16.  Shamalov K, Levy SN, Horovitz-Fried M , Cohen CJ^, The mutational status of p53 can influence its recognition by human T-cells. Oncoimmunology. 2017 Jan 31;6(4) . ( IF:  Citation:8, Q1)

1. Kesten D, Horovitz-Fried M, Brutman-Barazani T, Sampson SR ^.Insulin-induced translocation of IR to the nucleus in insulin responsive cells requires a nuclear translocation sequence. Biochim Biophys Acta. 2018 Apr;1865(4):551-559. (IF: 2.648, Citations:  Q1)

                     As a lab manager and as a researcher  I assisted the lab PI in planning and writing

                    various national and  international grants.

     2001-2003: Teaching assistant: cell physiology (undergraduate), Bar-Ilan University.

    2003-2006: Teaching assistant: physiology laboratory (undergraduate), Bar-Ilan University.

    2006-2007: Teaching assistant: biochemistery laboratory (undergraduate), Bar-Ilan University.

    2008- 2009: Lecturer: Endocrinolog  , Ariel university.

         2015-2017 :   Lecturer Regulation in gene expression , Ariel university.

        2011- 2017: Anatomy and Physiology, Nursing School, Lev academic center, Mivchar
                                  Campus.

2015-presest  Lecturer professionals  course in Health science , Or Yehuda college.

2015-present: volunteering in "Refua ve Haim" (Society of Medicine and Life)