Profile photo of Jairaj K. Acharya, MBBS, Ph.D.
Jairaj K. Acharya, MBBS, Ph.D.
Senior Investigator
Head, Sphingolipid and Phospholipid Signaling Section

Center for Cancer Research
National Cancer Institute

Building 560, Room 22-6
Frederick, MD 21702-1201
301-846-7051

Dr. Jairaj Acharya has a long standing interest in understanding how the in vivo functions of the enzymes involved in lipid metabolism are integrated with cellular and organismal homeostasis. His group was one of the first to show that modulation of the sphingolipid biosynthetic pathway could modulate neurodegenerative diseases. Using Drosophila and mouse models, his group is currently studying the role of the sphingolipid biosynthetic pathway in stem cell differentiation processes and their implications in disease processes.

Areas of Expertise
1) sphingolipids, 2) neurodegeneration, 3) genetics, 4) membrane biology, 5) Drosophila genetics

Phospholipid Signaling

Our long-term objective is to understand the complex interrelationship between phospholipid and sphingolipid metabolism and metabolic signaling in vivo. Intermediates of phospholipid (PL) and sphingolipid (SL) metabolism serve as second messengers for a number of signaling cascades including activation of G-protein-coupled receptors such as adrenaline and thrombin as well as receptor tyrosine kinases by growth factors. They mediate a number of processes ranging from protein secretion to activation of apoptosis. We have initiated studies to understand several aspects of lipid signaling in Drosophila.

Lipid Reservoirs and Signaling. Sphingomyelin (or phosphorylethanolamine ceramide, CPE, in flies) could serve as a reservoir for several lipid messengers such as ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. We have initiated studies to delineate the in vivo role of some of the enzymes of the putative "Sphingomyelin Cycle". We have begun by identifying homologous genes in Drosophila. We are using transgenic gain of function and mutagenic loss of function studies to analyze the importance of such a pathway in Drosophila. We have recently demonstrated that modulation of the sphingolipid biosynthetic pathway such as targeted expression of ceramidase, rescues degeneration in certain photoreceptor mutants. We have also demonstrated that ceramidase facilitates membrane turnover and rhodopsin endocytosis in Drosophila photoreceptors.

Sphingolipids are synthesized vectorially. While the steps that lead up to the generation of ceramide occurs in the endoplasmic reticulum (ER) the biosynthesis of sphingomyelin(or CPE) and most complex sphingolipids occurs outside of the ER, either in the Golgi Complex or in the plasma membrane. This necessitates the active transport of ceramide from ER to the Golgi Complex. The transport is largely mediated by a protein called ceramide transfer protein (CERT). We have now demonstrated that CERT-mediated transfer of ceramide is critical for the biosynthesis of sphingomyelin (or CPE in Drosophila) and complex sphingolipids. Lack of CERT in Drosophila leads to decreased CPE and they have plasma membranes with altered physical and physiological properties. The changes render them susceptible to normal loads of reactive oxygen species encountered in a cell. The ensuing oxidative damage of plasma membrane leads to production of lipid peroxides that will further oxidize membrane and cellular constituents leading to a rapid deterioration in the metabolic function of cell. The underlying pathoglogic changes manifest as accelerated aging in these mutant flies and consequently they have a short adult life span.

Lipid Distribution and Signaling. PL and SL at the plasma membrane play an important role in stimulus-response coupling, cell differentiation, movement, and exo- and endocytosis. They are asymmetrically distributed in biological membranes and different proteins catalyzing uni- and bidirectional movements of lipids perpetuate asymmetry. Our initial studies involving the generation and characterization of mutants of scramblases in Drosophila indicate a modulatory role for these proteins in regulated exocytosis and no determining role in scrambling of phospholipids. This has implications in a wide range of cellular processes. Further studies should enable us to dissect its role further.

Scientific Focus Areas:
Cell Biology, Genetics and Genomics, Neuroscience
  1. Kosakowska-Cholody T, Lin J, Srideshikan SM, Scheffer L, Tarasova NI, Acharya JK.
    Cell Death Dis. 5: e1240, 2014. [ Journal Article ]
  2. Rao RP, Scheffer L, Srideshikan SM, Parthibane V, Kosakowska-Cholody T, Masood MA, Nagashima K, Gudla P, Lockett S, Acharya U, Acharya JK.
    PLoS ONE. 9: e92142, 2014. [ Journal Article ]
  3. Rahman M, Nirala NK, Singh A, Zhu LJ, Taguchi K, Bamba T, Fukusaki E, Shaw LM, Lambright DG, Acharya JK, Acharya UR.
    J. Cell Biol. 2014. [ Journal Article ]
  4. Kunduri G, Yuan C, Parthibane V, Nyswaner KM, Kanwar R, Nagashima K, Britt SG, Mehta N, Kotu V, Porterfield M, Tiemeyer M, Dolph PJ, Acharya U, Acharya JK.
    J. Cell Biol. 206: 79-95, 2014. [ Journal Article ]
  5. Masood MA, Rao RP, Acharya JK, Blonder J, Veenstra TD.
    Lipids. 47: 209-26, 2012. [ Journal Article ]

Dr. Jairaj Acharya obtained his M.B.B.S. from the University of Gulbarga (Government Medical College, Bellary), India, in 1985 and received his Ph.D. in biochemistry from the Indian Institute of Science, Bangalore, in 1993 under Prof. Appaji Rao. He joined Dr. Charles Zuker at the University of California, San Diego as an associate of the Howard Hughes Medical Institute for his postdoctoral training. He was recruited by the NCI in 1999.

Position Number of Positions Contact E-mail Contact Name Contact Phone
Postdoctoral Fellow 1

acharyaj@mail.nih.gov

Dr. Jairaj Acharya 301-846-7051
Name Position
Teresa Kosakowska-Cholody M.S. Research Biologist
Govind Kunduri Postdoctoral Fellow (Visiting)
Jing Lin Ph.D. Postdoctoral Fellow (CRTA)
Brigdet Njeri Special Volunteer
Katherine Nyswaner Research Biologist
Srideshikan Sargur Madabushi Postdoctoral Fellow (Visiting)
Parthibane Velayoudame Postdoctoral Fellow (Visiting)

Summary

Dr. Jairaj Acharya has a long standing interest in understanding how the in vivo functions of the enzymes involved in lipid metabolism are integrated with cellular and organismal homeostasis. His group was one of the first to show that modulation of the sphingolipid biosynthetic pathway could modulate neurodegenerative diseases. Using Drosophila and mouse models, his group is currently studying the role of the sphingolipid biosynthetic pathway in stem cell differentiation processes and their implications in disease processes.

Areas of Expertise
1) sphingolipids, 2) neurodegeneration, 3) genetics, 4) membrane biology, 5) Drosophila genetics

Research

Phospholipid Signaling

Our long-term objective is to understand the complex interrelationship between phospholipid and sphingolipid metabolism and metabolic signaling in vivo. Intermediates of phospholipid (PL) and sphingolipid (SL) metabolism serve as second messengers for a number of signaling cascades including activation of G-protein-coupled receptors such as adrenaline and thrombin as well as receptor tyrosine kinases by growth factors. They mediate a number of processes ranging from protein secretion to activation of apoptosis. We have initiated studies to understand several aspects of lipid signaling in Drosophila.

Lipid Reservoirs and Signaling. Sphingomyelin (or phosphorylethanolamine ceramide, CPE, in flies) could serve as a reservoir for several lipid messengers such as ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. We have initiated studies to delineate the in vivo role of some of the enzymes of the putative "Sphingomyelin Cycle". We have begun by identifying homologous genes in Drosophila. We are using transgenic gain of function and mutagenic loss of function studies to analyze the importance of such a pathway in Drosophila. We have recently demonstrated that modulation of the sphingolipid biosynthetic pathway such as targeted expression of ceramidase, rescues degeneration in certain photoreceptor mutants. We have also demonstrated that ceramidase facilitates membrane turnover and rhodopsin endocytosis in Drosophila photoreceptors.

Sphingolipids are synthesized vectorially. While the steps that lead up to the generation of ceramide occurs in the endoplasmic reticulum (ER) the biosynthesis of sphingomyelin(or CPE) and most complex sphingolipids occurs outside of the ER, either in the Golgi Complex or in the plasma membrane. This necessitates the active transport of ceramide from ER to the Golgi Complex. The transport is largely mediated by a protein called ceramide transfer protein (CERT). We have now demonstrated that CERT-mediated transfer of ceramide is critical for the biosynthesis of sphingomyelin (or CPE in Drosophila) and complex sphingolipids. Lack of CERT in Drosophila leads to decreased CPE and they have plasma membranes with altered physical and physiological properties. The changes render them susceptible to normal loads of reactive oxygen species encountered in a cell. The ensuing oxidative damage of plasma membrane leads to production of lipid peroxides that will further oxidize membrane and cellular constituents leading to a rapid deterioration in the metabolic function of cell. The underlying pathoglogic changes manifest as accelerated aging in these mutant flies and consequently they have a short adult life span.

Lipid Distribution and Signaling. PL and SL at the plasma membrane play an important role in stimulus-response coupling, cell differentiation, movement, and exo- and endocytosis. They are asymmetrically distributed in biological membranes and different proteins catalyzing uni- and bidirectional movements of lipids perpetuate asymmetry. Our initial studies involving the generation and characterization of mutants of scramblases in Drosophila indicate a modulatory role for these proteins in regulated exocytosis and no determining role in scrambling of phospholipids. This has implications in a wide range of cellular processes. Further studies should enable us to dissect its role further.

Scientific Focus Areas:
Cell Biology, Genetics and Genomics, Neuroscience

Publications

  1. Kosakowska-Cholody T, Lin J, Srideshikan SM, Scheffer L, Tarasova NI, Acharya JK.
    Cell Death Dis. 5: e1240, 2014. [ Journal Article ]
  2. Rao RP, Scheffer L, Srideshikan SM, Parthibane V, Kosakowska-Cholody T, Masood MA, Nagashima K, Gudla P, Lockett S, Acharya U, Acharya JK.
    PLoS ONE. 9: e92142, 2014. [ Journal Article ]
  3. Rahman M, Nirala NK, Singh A, Zhu LJ, Taguchi K, Bamba T, Fukusaki E, Shaw LM, Lambright DG, Acharya JK, Acharya UR.
    J. Cell Biol. 2014. [ Journal Article ]
  4. Kunduri G, Yuan C, Parthibane V, Nyswaner KM, Kanwar R, Nagashima K, Britt SG, Mehta N, Kotu V, Porterfield M, Tiemeyer M, Dolph PJ, Acharya U, Acharya JK.
    J. Cell Biol. 206: 79-95, 2014. [ Journal Article ]
  5. Masood MA, Rao RP, Acharya JK, Blonder J, Veenstra TD.
    Lipids. 47: 209-26, 2012. [ Journal Article ]

Biography

Dr. Jairaj Acharya obtained his M.B.B.S. from the University of Gulbarga (Government Medical College, Bellary), India, in 1985 and received his Ph.D. in biochemistry from the Indian Institute of Science, Bangalore, in 1993 under Prof. Appaji Rao. He joined Dr. Charles Zuker at the University of California, San Diego as an associate of the Howard Hughes Medical Institute for his postdoctoral training. He was recruited by the NCI in 1999.

Positions

Position Number of Positions Contact E-mail Contact Name Contact Phone
Postdoctoral Fellow 1

acharyaj@mail.nih.gov

Dr. Jairaj Acharya 301-846-7051

Team

Name Position
Teresa Kosakowska-Cholody M.S. Research Biologist
Govind Kunduri Postdoctoral Fellow (Visiting)
Jing Lin Ph.D. Postdoctoral Fellow (CRTA)
Brigdet Njeri Special Volunteer
Katherine Nyswaner Research Biologist
Srideshikan Sargur Madabushi Postdoctoral Fellow (Visiting)
Parthibane Velayoudame Postdoctoral Fellow (Visiting)