Basic Research on Molecular Genetics mostly focused on muscular diseases
Hereditary Inclusion Body Myopathy: Characterization of the effects of the mutated GNE gene in the pathophysiology of muscle tissue.
Hereditary Inclusion Body Myopathy (HIBM) is a unique group of neuromuscular disorders characterized by adult-onset, slowly progressive distal and proximal muscle weakness, and typical muscle pathology, including rimmed vacuoles and filamentous inclusions. This disease is the most common form of ethnic-related familial degenerative myopathy, with a prevalence of 1:1500 in the Jewish Iranian community. The identification in our laboratory of GNE as the gene causing HIBM, a form of myopathy till then considered almost exclusively as a Middle Eastern Jewish disease, allowed the recognition of that same disorder worldwide and a new classification of this group of diseases.
UDP-N-acetylglucosamine2-epimerase/ N-acetylmannosamine kinase (GNE) is a bifunctional enzyme which plays a key role in the biosynthetic pathway of sialic acid. Because of its terminal position on macromolecules and on cell membranes, sialic acid is an essential molecule involved in many biological and pathological processes.
Our research is now aimed towards the understanding of the biochemistry and biology of GNE in non affected muscle, and subsequently in HIBM muscle tissue, by investigating different biochemical and biological aspects of the GNE activity in muscle tissue and cell cultures. Transgenic animals will also be established bearing the mutated gene. Simultaneously we are investigating the potential partners of GNE in muscle cells by mass spectrometry, and microchip technology.
We anticipate that these in vitro and in vivo systems specifically designed for a genomic and proteomic approach will provide us with the necessary tools to unravel the mechanisms of GNE protein in normal muscle tissue and possible steps for the eventual correction of the mutation effect in HIBM.
Identification of genes involved in hereditary cardiomyopathies
Recently, several transcription factors have been implicated in the complex biological process of cardiac development. An approach to the understanding of some of the steps involved is the identification of human mutations that cause congenital heart disease. In collaboration with Dr Annick Raas Rothschild from the Department of Human Genetics and Dr Azaria Rein from the Department of Pediatric Cardiology, we are analyzing various families affected by congenital cardiac diseases.
Molecular markers for the detection of breast and colon cancer micrometastases in axillary lymph nodes
Micrometastases in axillary lymph nodes have been detected by serial sectioning and immunohistochemistry., and shown to have prognostic significance. When compared to node-negative disease, the presence of even a single micrometastasis in a lymph node, is associated with a significant difference in recurrence and survival, and therefore will determine the nature of the treatment to follow. In collaboration with Dr Aviram Nissan, from the Department of Surgery at Mount Scopus, we are developing assays for an increased rate of detection of tumor involvement within an excised node, by the measurement of differentially expressed gene transcripts, using a Real Time PCR amplification methods.