- ASSISTANT PROFESSOR Genetics and Genomic Sciences
BSc, Bar Ilan University
MSc, Tel-Aviv University Medical School
PhD, Tel-Aviv University Medical School
The Mount Sinai Medical Center
- Mailing Address:
Department of Genetics and Genomic Sciences,
1425 Madison Ave, room 14-26A
New York, NY 10029
ResearchAssess the benefits of AC activity and inhibition. Acid ceramidase (AC) is required to hydrolyze the signaling lipid, ceramide, into sphingosine and free fatty acids. The production of ceramide in cell membranes leads to reorganization of "raft" structures, activation of signaling proteins, and the initiation of apoptosis. Sphingosine is rapidly converted to sphingosine-1-phosphate (S1P), another important signaling lipid that counteracts the effects of ceramide and promotes cell survival. Importantly, AC also synthesizes ceramide from sphingosine and free fatty acids (i.e., the "reverse" reaction). Thus, AC is a "rheostat" that regulates the levels of ceramide and S1P in cells, and as such participates in the complex and delicate balance between death and survival. Importantly, inherited mutations in the AC gene cause the severe lipid storage disorder, Farber disease. Infants with Farber disease develop multiple abnormalities within the first few weeks of life, including deformed joints, progressive hoarseness, subcutaneous nodules, and severe motor and mental retardation. Most die by 2 years of age. Several cases of Farber disease presenting as "hydrops fetalis" also have been reported.
We have previously shown that AC expression is carefully regulated during egg maturation and early embryo development. We have also found that the complete "knock-out" of AC function in mice leads to embryo death between the 2 and 8-cell stage (FASEB J, 2007).
Examine the role of AC in mouse development by studying conditional AC knock-out mice"Floxed" AC knock-out animals have already been produced. We will breed these animals to transgenic mice in which the activity of Cre recombinase in the nucleus is under the control of tamoxifen, and induce the AC knock-out at various pre- and postnatal stages. Analysis of these embryos and mice should better define the precise in vivo role of AC in apoptosis and organ-specific development.
Study the biochemical mechanisms leading to AC activation and translocation from lysosomes to the cell membrane
The production of active AC requires cleavage of a precursor molecule into alpha and beta subunits. We have found that AC has the unique ability to undergo self-cleavage, and identified the specific amino acids that are required for this function. We will now explore factors regulating this self-cleavage event (e.g., pH, subcellular location, ceramide and S1P levels, etc), as well as how cleavage affects the "reverse" AC activity. We will also use confocal microscopy to study whether AC translocates from lysosomes to the cell surface upon the initiation of cell signaling, and investigate factors governing this translocation event (e.g., phosphorylation).
Investigate the function of AC in female germ cell development
It has been shown that as mouse eggs age in vitro, the levels of ceramide increase. We have found that it is due to a reduction of AC activity. Upon fertilization, AC activity increases in the newly formed embryos, reducing ceramide levels and inhibiting apoptosis. To extend these findings we will now obtain eggs from young and old female mice, and compare ceramide, S1P and AC levels. We will also examine the effects of recombinant AC and AC gene expression on egg and embryo survival in vitro.
Simonaro CM, D'Angelo M, He X, Eliyahu E, Shtraizent N, Haskins ME, Schuchman EH. Mechanism of glycosaminoglycan-mediated bone and joint disease: implications for the mucopolysaccharidoses and other connective tissue diseases. Am. J. Pathol 2008; 172(1): 112-122.
Shtraizent N, Eliyahu E, Park JH, He X, Shalgi R, Schuchman EH. Autoproteolytic cleavage and activation of human acid ceramidase. J. Biol. Chem 2008; 283(17): 11253-11259.
Eliyahu E, Park JH, Shtraizent N, He X, Schuchman EH. Acid ceramidase is a novel factor required for early embryo survival. FASEB J. 2007; 21(7): 1403-1409.
Tsaadon A, Shalgi R, Shtraizent N, Eliyahu E. When a sperm meets an egg: block to polyspermy [review]. Mol Cell Endocrinol 2006; 252(1-2): 107-114.
Simonaro CM, Park JH, Schuchman EH, Shtraizent N, McGovern MM, Eliyahu E. Imprinting at the SMPD1 locus: implications for acid sphingomyelinase-deficient Niemann-Pick disease. Am J Hum Genet 2006; 78(5): 865-870.
Park JH, Eliyahu E, Schuchman EH, DiFeo A, Martignetti JA, Narla G. KLF6 is one transcription factor involved in regulating acid ceramidase gene expression. Biochim Biophys Acta 2006; 1732: 82-87.
Eliyahu E, Shalgi R, Tsadon A, Shtraizent N. Association between myristoylated alanin-rich C kinase substrate (MARCKS) translocation and cortical granule exocytosis in rat eggs. Reproduction 2006; 131(2): 221-231.
Eliyahu E, Shalgi R, Shtraizent N, Tsadon A. The involvement of protein kinase C and actin filaments in cortical granules exocytosis in the rat. Reproduction 2005; 129(2): 161-170.
Talmor-Cohen A, Tomashov-Matar R, Shalgi R, Shapiro R, Eliyahu E. Are Src family kinases involved in cell cycle resumption in rat eggs?. Reproduction 2004; 127(4): 455-463.
Shalgi R, Eliyahu E. Role of protein kinase C isozymes in mammalian egg activation. Biology of Reproduction 2002; 67: 189-195.
Talmor-Cohen A, Shalgi R, Eliyahu E. Signalling in mammalian egg activation: role of protein kinases [review]. Molecular and Cellular Endocrinology 2002; 187: 145-149.
Eliyahu E, Shalgi R, Talmor- Cohen A. Signaling during egg activation and protein kinases. J. Reprod Immunol 2002; 53(1-2): 161-169.
Talmor A, Eliyahu E, Shalgi R. Signal transduction pathways in activation of the mammalian egg [review]. Italian Journal of Anatomy and Embryology 2001; 106: 43-49.
Eliyahu E, Kaplan-Kraicer R, Shalgi R. PKC in eggs and embryos [review]. Frontiers in Bioscience 2001; 6: d785-791.
Raz T, Eliyahu E, Shalgi R. Profile of PKC isozymes and their possible role in mammalian egg activation. FEBS Letter 1998; 431: 415-418.
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Dr. Eliyahu did not report having any of the following types of financial relationships with industry during 2014 and/or 2015: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
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