Research in this department focuses on the utilization of molecular genetics for the study of diverse biological processes, including the study of viruses, control of cell growth and death, cytokines and receptors, human genetic disorders, gene expression, intracellular trafficking and development. One major theme is the use of genetics of model organisms and cell culture genetics, to dissect the role of genes in the context of the whole animal. Another focus of the department is on genomics and bioinformatics. Utilization of quantitative approaches is crucial for analysis of the wealth of information provided by the completed genome sequences and the accumulating gene expression data from DNA arrays.

N. Barkai

Developing new computation tools for analyzing large-scale gene expression data ("DNA chips").

Quantitative study and modeling of morphogen gradients in Drosophila.

A. Elson

Analysis of the role of protein tyrosine phosphatase Epsilon (PTPe) in mouse physiology and tumorigenesis using PTPe-knockout mice. Special emphasis on role of PTPe in myelination of axons in the central and peripheral nervous systems.

PTPe action at the molecular level: Identification of substrates and interactors of PTPe, and understanding the details and consequences of their interaction with PTPe.

J.E. Gerst

Use of yeast and nematodes as model systems to understand how eukaryotic cells deliver proteins and lipids to and from the cell surface: Molecular dissection of the late secretory pathway.

1. Role of SNAREs (vesicle fusion proteins) and SNARE regulators in exocytosis and endocytosis.

2. Role of phosphorylation in SNARE assembly and membrane fusion.

3. Biogenesis of secretory vesicles and the mechanism of their docking and fusion.

O. Gileadi

The mechanism of transcription in yeast: Genetic and biochemical analysis.

Transcription factor TFIIH: A possible link between transcription, DNA repair, and the cell cycle.

Y. Groner

Molecular genetics of Down syndrome.

Transgenic and Knock-out mice models for gene dosage effect of Down Syndrome.

The Human Leukemia Associated Transcription Factor RUNX1/AML1 and Down syndrome leukemia.

C. Kahana

Characterization of the regulation and role of polyamines during growth of mammalian cells

1. Regulation of ornithine decarboxylase expression.

2. Polyamines and apoptosis.

Identification and characterization of regulatory and structural components of the polyamine transport system.

1. Characterization of the proteolytic machinery.

2. Characterization of ornithine decarboxylase sequences that mediate its recognition by the proteolytic machinery.

Identification and characterization of functional domains of mammalian ornithine decarboxylase.

Characterization of ornithine decarboxylase degradation.

A.M. Kaye

Control of expression of the gene for creatine kinase B by hormones and growth factors.

Action of new selective estrogen receptor modulators against breast cancer and osteoporosis.

Use of engineered mutants of parathyroid hormone as anabolic agents for bone growth and repair.

A. Kimchi

Deciphering molecular networks underlying apoptosis and other basic biological processes.

1. Structure/function studies of DAP genes - a set of pro-apoptotic proteins isolated by a functional approach to gene cloning.

2. Implication of DAP genes in cancer development and in the control of cellular events such as protein translation initiation, and cytoskeletal organization.

3. Function-based gene "hunting" and the development of novel strategies to identify the basic principles of complex molecular networks.

D. Lancet

Genomic and evolutionary analyses of molecular recognition systems.

1. Identification and molecular cloning of members of the olfactory receptor multigene family, including studies of their genome organization, evolution and polymorphisms in humans.

2. Computer analyses of structural models of olfactory receptors and other transmembrane proteins and of receptor affinity distributions.

3. Bioinformatics analysis of long-range DNA sequences and development of whole-genome databases.

4. Computer simulations of selection and evolution in current living organisms and at the origin of life.

P. Lonai

The role of FGF signaling in mammalian development.

FGF growth factors and their tyrosine kinase receptors contribute to most steps of development. They are active in wound healing, angiogenesis and osteogenesis, as well as in congenital bone anomalies and cancer.

We pursue two lines of research. One investigates cellular and molecular mechanisms that underline the morphogenic effects of FGF signaling through in vitro models, whereas the second uses gene targeting. We create point mutations of FGFR splice variants to provide in vivo models for limb, lung and bone development.

1. Our working hypothesis connects the FGF system with basement membrane formation. Basement membranes separate epithelia and mesenchymes and mediate their interaction, which is a developmental mechanism of central importance. We find that FGF signaling regulates the synthesis of laminin-1 and collagen IV through protooncogenes of the Pi 3-kinase pathway. These proteins form the mat-like framework of the basement membrane.

2. We created mouse models for human achondroplasia, craniosynostosis and tetra-amelia (limb and lung development defects). These strains can be used to test pharmacological agents to cancer and achondroplastic dwarfism. They also demonstrate the cooperation of different FGFR and may shed light on the mechanism of epithelial mesenchymal interactions.

S. Pietrokovski

Developing computational methods for using and identifying protein motifs and applying them for the analysis of particular protein families.

1. Developing advanced methods for comparing protein motifs.

2. Applying protein motif comparisons for functional and structural predictions and to database annotation.

3. Analysis of inteins ("protein splicing" elements) and homing endonucleases.

O. Reiner

Functional Analysis of Genes Involved in Lissencephaly.

Formation of the brain structure in human is a complex process. One of the most striking features of the human brain is characteristic convolutions. These convolutions are lacking in a severe human brain malformation known as lissencephaly (smooth brain). Lissencephaly patients have a severe mental retardation. So far, two genes have been found to be mutated in lissencephaly; LIS1 located on chromosome 17 and Doublecortin (DCX) an X-linked gene. Among our current projects:

1. Identification of genes that are downstream to Lis1 mutation using microarray technology.

2. Study of LIS1 and DCX function through characterization of protein-protein interactions, and overexpression in tissue culture.

3. Analysis of the developmental function of LIS1, DCX and Doublecortin-like-kinase using gene targeting in the mouse.

M. Revel, J. Chebath

Interleukin-6 Chimera, a superactivator of the gp130 receptor system: role in nerve myelination, neuroprotection and in the development of neuro-glial cells from embryonic tissues and stem cells.

Transdifferentiation of neural crest cell derived melanoma into myelinating Schwann cell. Genes controlling cell growth, differentiation, melanogenesis and synthesis of myelin proteins.

Applications of IL-6 Chimera and Interferon-beta in neurology, hematopoiesis, and oncology.

M. Rubinstein, D. Novick

Interleukin-18 binding protein: Structure and Function.

M. Rubinstein

Role of leptin in angiogenesis and fertility.

Regulation of HIF-1a expression and activation.

L. Sachs

Molecular control of hematopoiesis and leukemia

1. Cytokine and apoptosis gene networks in development and cancer.

2. Control of apoptosis, cell multiplication and differentiation.

3. Clinical applications of hematopoietic cytokines and apoptosis genes.

E. Schejter

1. Functional elements of the cytoskeleton in the early Drosophila embryo. We have identified and characterized mutant alleles of the gene centrosomin, which encodes an essential component of embryonic centrosomes. Our analysis suggests that conventional microtubule organizing centers are not required for progression of mitotic division cycles. However, centrosomes act as essential instructive elements governing reorganization of cortical microfilaments in the early embryo. This interaction between the microtubule and microfilament-based cytoskeletons is dependent on the gene sponge. We have cloned sponge and are currently characterizing the structure and function of its protein product.

2. Molecular genetic studies of the Drosophila homologs of the WASP/SCAR family of cytoskeletal elements. This evolutionarily conserved family acts as a key link, bridging various signal transduction pathways and the actin-based cytoskeleton. We have studied the Drosophila homologs of both WASP and SCAR, and have identified and characterized mutant alleles in both genetic loci. Drosophila SCAR participates in a wide variety of developmental processes involving changes in cellular morphology. The Drosophila WASP homolog is required in a surprisingly specific developmental context, namely, during execution of cell-fate decisions underlying development in the peripheral nervous system and other tissues.

Y. Shaul

Transcription regulation of the hepatitis B virus (HBV); promoters, enhancers and transcription factors.

Mechanism of action of viral regulators; the X prof HBV as a transcription coactivator and the Nef protein of HIV as a protein histidine-kinase.

The role of c-Abl protein tyrosine-kinase in RFX1- mediated transcription regulation and in p73-mediated apoptosis under DNA-damage stress.

Gene therapy by DNA-correction and protein transduction.

B. Shilo

Signaling by the Drosophila EGF receptor pathway during development.

Development of the Drosophila tracheal system.

R. Simantov

Molecular mechanisms controlling neuronal cell death and drug addiction

1. Programmed cell death in the brain: Genes activated by neuroactive agents working via neurotransporters.

2. Involvement of serotonin transporters in neuronal plasticity, growth and neurotoxicity; studies with knockout mice.

3. Reward and reinforcement mechanisms in the nervous system: Interactions with dopamine, serotonin and glutamate networks.

T. Volk

The molecular basis for muscle-tendon interactions during embryonic development

1. The mechanism by which the RNA-binding protein "How" controls tendon cell differentiation.

2. Local activation of the Vein/EGF receptor pathway by localization of Vein at the sites of cell-cell contacts.

3. Structure-function analysis of Kakapo, a cross-linker between the actin and the microtubule networks in tendon cells.