University Education and Additional Training

 

2005 – 2008

B.Sc. in Life Sciences at Tel Aviv University.

2008 – 2009

M.Sc. in Neurobiochemistry at Tel Aviv University.

Rotation year of the Dean’s List Honors program for outstanding students.

Supervision by: Prof Yoel Kloog

2009 – 2013

Ph.D. in Neurobiochemistry at Tel Aviv University.

Title of thesis: Design and development of a novel LIMK inhibitor as a potential cancer drug.

Supervision by: Prof. Yoel Kloog

 2013 – 2015

Postdoctoral position at Tel Aviv University with Prof. Oded Rechavi

Research subject: Linking translation to protein misfolding

2015 – 2016

Postdoctoral position at Weizmann Institute  with Prof. Yitzhak Pilpel

Research subject:  regulation of translation in proliferating and differentiated mammalian cells

2016 – 2020

Senior intern position at Weizmann Institute  with Prof. Yitzhak Pilpel

Research subject: regulation of translation in proliferating and differentiated mammalian cells

 

Positions Held and Academic Status

2021 – present

Research Scientist (Rank C, equivalent to "Lecturer") at the ARO, The Volcani Center, Institute of Aminal Sciences

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Scientific Contribution

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Ph.D. period under Prof. Yoel Kloog at Tel-Aviv University

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Metastasis drug development

My Ph.D. focused on novel drug development for cancer and Neurofibromatosis. We hypothesize that targeting LIM kinase, an enzyme that regulates cell cytoskeleton formation, will reduce cell motility and cancer metastasis. LIM kinase phosphorylates and inhibits cofilin- actin depolymerization factor and is hyperactivated by Rho and Rac-1 proteins, in neurofibromin (NF1) depleted cells. In collaboration with Efrat Mashiach-Farkash, we used an innovative computational screen that utilized the 3D structure of the enzyme to search for proteins that carry a resembling active site. Based on this approach we could repurpose an existing molecule to target LIMK and reduce its activity. We found that the drug reduces cell cytoskeleton formation and cell motility in cells deficient in NF1, and several cancer types. Furthermore, treatment of mice with the drug blocks cancer formation in pancreatic cancer. Based on our success in an animal model, we issued a US patent.

 

Postdoctoral period under Prof. Oded Rechavi at Tel-Aviv University

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tRNA regulation in development and aging

My first Postdoctoral project was devoted to exploring the link between translation fidelity/efficiency and protein misfolding. The availability of mature tRNA affects translation rates, proper protein folding, and even mRNA stability. The spatial-temporal- regulation of tRNA is crucial for governing the integrity of the proteome. Yet exploring tRNA expression in specific tissues within the intact organism by using reporter proteins (such as GFP) is a challenging task. tRNAs are transcribed by Pol III, which can only transcribe short sequences (much shorter than a typical fluorescent reporter), and depends on tRNA-intrinsic sequences for expression. 

During my Postdoctoral, In collaboration with Dr. Dror Sagi, I have designed and built a novel reporter system that allows to track the expression of individual tRNA genes in live C. elegans nematodes using cell-specific fluorescent signals. Although the dogma states that tRNA expression is exclusively regulated by intrinsic control elements (A- and B- box sequences), our data revealed that six Trp-tRNA genes, 100% identical in sequence, are expressed in different tissues and dynamically change their expression during development and aging. Furthermore, expression levels of one of these tRNA genes at young adulthood were predictive of the animal’s lifespan. We further found that the differential expression of tRNAs that reside within introns of protein-coding genes is dependent on the host gene’s promoter.

 

Postdoctoral and scientist (senior intern) period under Prof. Yitzhak Pilpel at Weizmann Institute

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In my second postdoctoral research and as a senior scientist, I took a systemic approach to characterize the translation machinery and tRNA pool changes across evolution, across development, and in changing physiological states.

 

Translation in proliferation and differentiation

My main project was aimed at understanding the role played by tRNAs in mammalian cells differs in proliferation and differentiation status. Previous work from the Pilpel lab uncovered a dual translational program in proliferating cancer cells and differentiated cells (Gingold et al. cell, 2014).  Building on this work that focused mainly on cancer cells and artificial model systems,  I wanted to study the changes in the tRNA pool and demand for codon, dictated by mRNA expression, in natural physiologically relevant proliferation programs. The immune system, in particular T-cells, provides an ideal system to study this question. T-cells undergo vigorous proliferation followed by the differentiation step upon triggering of the T cell antigen receptor. We developed a new method to deep-sequence tRNA molecules and used it to follow the tRNA pool during this process. We found that mRNA demand for codons changes in a coordinated manner with tRNA availability in the early activation state of the cells. In addition, we developed a bioinformatic pipeline enabling us to deduce RNA modifications on tRNA molecules from tRNA deep sequencing results. We found dynamic changes in tRNA modifications that are likely to affect translation rate and fidelity, and cause aberrant protein translation in highly proliferating T-cells.

Next, to explore the causality between tRNA availability and cellular proliferation we developed a CRISPR/iCas9 system to target tRNA genes. We then used it to target two different sets of tRNAs differentially expressed during either proliferation or differentiation. We measured the essentiality of those tRNA in several cultured cell lines differing in their proliferation rate and cancerous status. This work revealed that tRNAs that are induced in proliferation are more essential in rapidly growing cell lines compared to tRNA induced in differentiation. We further study the effect of tRNA depletion in cellular arrest and found a different subset of tRNAs that are involved in entering quiescence and senescence.

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Translation fidelity

translation errors are frequent and can affect physiology and protein evolution. We developed the first methodology for systematic detection and quantification of errors through the proteome. Applying our pipeline on yeast and E.coli proteomes revealed that translation mistakes are not random but rather tend to occur at positions that are less evolutionarily conserved, minimally affect protein stability, and are fastly translated.  Furthermore, we found that most substitutions result from codon-anticodon mispairing rather than tRNA mischarging.

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Experimental evolution

To assess different approaches scientists use in experimental evolution, we organized a community challenge- Evolthon.  With scientists from multiple labs across the world, we evolved E. coli and S. cerevisiae in parallel using diverse environmental and genetic regimes toward dealing with the stress of low temperatures. My team used an approach we termed  “caching cold RNA” in which we reverse transcribed the mRNAs of yeast cultured under cold conditions and integrated it back to untreated yeast genome to create duplicated genes in the genome. After the evolution period, strains from all teams were evaluated based on their successful growth in low temperatures as well as other challenges. We were able to recognize strategies that were most successful for the desired challenge and strategies that improved cell growth in various conditions.