Aerobic organisms employ a family of metalloenzymes known as Superoxide Dismutase (SOD) to scavenge superoxide anions (O2-); the highly reactive oxygen species generated by univalent reduction of molecular oxygen during cellular respiration. SODs essentially dismutate O2- to hydrogen peroxide (H2O2) that is converted to H2O by Catalase and Peroxidase. O2- radicals are damaging to cellular constituents because these radicals attack proteins, nucleic acids and membrane lipids, thereby disrupting cellular function and integrity. The cumulative effect of this cellular damage contributes to many cellular pathologies including mutagenesis, carcinogenesis, diabetes, neurodegenerative disease, inflammatory diseases, as well as to the overall process of cellular senescence organismal aging proces. I am using the fruitfly, Drosophila melanogaster as a model organism in my laboratory, since Drosophila offers a well-defined reproductive, developmental, behavioral and molecular genetic system. Drosophila carries two forms of SOD: the copper-zinc SOD (Cu-ZnSOD), which is cytoplasmic, and the Manganese SOD (MnSOD), which acts in mitochondria. Null mutants for Cu-ZnSOD in Drosophila show reduced viability and most importantly, Cu-ZnSOD null mutants have neuropathology and reduced motor activity. The Drosophila MnSOD gene is now well characterized (Duttaroy et al., 1994; Duttaroy et al., 1997; Duttaroy et al., 2003) although the biological role of MnSOD remains virtually unexplored. MnSOD function must be vital to the cell, since MnSOD activity is restricted to the principal cellular radical generating organelle, the mitochondria. The interest of my laboratory will be geared towards understanding MnSOD gene function by using following molecular genetic tools available in Drosophila:

 ·  Genetic characterization of the Mn SOD gene functions in Drosophila. Both Loss of function mutation as well as hypomorphic mutations for MnSOD function were isolated. MnSOD mutants will be important to explore the biology of this primary defense system against oxidative stress.

 ·  Targeted over expression, tissue specific misexpression, and tissue specific loss of MnSOD function will help us to explore the biology of this primary defense system against oxidative stress.

·  Relationship between MnSOD function and neuromuscular degeneration.

Research Funding (Active):

·  National Institutes of Health.  Title: Manganese superoxide dismutase in mechanisms of aging and neurodegeneration. 2 U54 NS039407-06A1.  2006-2010.

Project Goal: The critical connection between oxidative damage and neurodegeneration remains elusive.  An oxidative damage protection system is essential ubiquitously in the mitochondria of all aerobic organisms, as evident from the fact that lack of mitochondrial SOD activity reduces the life span in all organisms studied.  We hypothesize that reduced MnSOD activity should initiate neuromuscular degeneration at an earlier age and that degeneration ought to be progressive in nature.  Our preliminary results support this hypothesis since reduction in MnSOD activity is associated with progressive reduction in motor ability, presumably due to the massive neuronal loss that these flies suffer.  A MnSOD null (Sod2ⁿ²⁸³) and a weak allele (Sod2^wk) and their combinations provide us with a unique model to study the effects of oxidative stress on neuromuscular ability, cognition, neurodegeneration, and how it influences natural aging.

 ·  National Institutes of Health.  Title: ROS induced cellular toxicity and tissue damage assessment.  1R15 AG025754-01.  3/1/06 to 2/29/09.

Project Goal: The specific hypothesis to be tested is that depletion of MnSOD activity from a specific tissue will trigger cellular damages through an intracellular rise in ROS concentration; however, the amount of damage to individual tissues will vary, as will their biological efficacies, which will be reflected at the organismal level. We will examine our hypothesis in four different tissues in Drosophila including fat body, muscle, brain and retinal cells of the eye, all of which are essential for the viability of the organism with the exception of retinal cells.  By using a state-of-the-art technique MnSOD function will be depleted in vivo from each of these tissues.

Funding (Completed):

·  National Institutes of Health. Title: Manganese superoxide dismutase and in vivo aging (supplement). R15 AG17846-01S1. 9/1/2002 to 8/31/2003.

·  National Institutes of Health. Manganese superoxide dismutase and in vivo aging.  # 1R15 AG 17846-01. 9/01/00 to 8/31/03.

·  American Federation for Aging Research (AFAR) Genomic regions involved in Manganese superoxide dismutase regulation in Drosophila melanogaster.  6/01/01 to 5/31/03.

Selected peer-reviewed publications (in chronological order).

 ·  Dora Dias-Santagata, Atanu Duttaroy and Mel B. Feany “Tau-induced neurodegeneration is modulated by oxidative stress and activates the JNK pathway in Drosophila.” Journal of Clinical Investigation (In Press).

·  Belton A, Paul A, and Duttaroy A (2006) Deletions encompassing the Manganese Superoxide Dismutase gene in the Drosophila melanogaster. Genome 49: 746-749

·  Duttaroy, A., Paul, A., Kundu, M., and Belton, A (2003) A Sod2 null mutation confers severely reduced adult life span in Drosophila.  Genetics 165:2295-2299.  (see also perspective by J Tower ‘There is a problem in the furnace in Sci. Aging. Knowl. Environ 2004 (1), pe 1 (2004).

·  Paul, A., and Duttaroy, A (2003) Genomic regions responsible for Manganese superoxide dismutase regulation in Drosophila melanogaster.  Aging Cell 2: 223-231. (see also cover photograph)

·  Duttaroy  A (2002) Asymmetric exchange is associated with P element induced male recombination in Drosphila melanogaster.  Heredity 89:114-119.

·   Wanga J, Duttaroy A, and Anderson WA (2002) Expression of NK2 homologous transcripts during zebrafish development.  J. submicrosc. Cytol. Pathol. 34: 233-239.

Research Team

Graduate students, Postdocs, and Technicians

Ms. Catherine Martin: MS degree student. MS Thesis completed in May 2005. Dissertation Title” A Search for Novel X-linked mutations that Increase Drosophila melanogaster Life Span.”

Mr. Aniban Paul:  Ph. D Thesis completed in December 2005.  Dissertation Title” In Vivo Regulation of Manganese Superoxide Dismutase cativity and Its Role in Aging and Neurodegeneration in Drosophila melanogaster”.

Ms. Amy Belton: Ph. D degree student (current).

Rene Forde: Ph. D student (current).

Kristopher Beckwith: MS student (current).

Subhas Mukherjee: Ph. D student (current).

Sanjay Nag: Postdoctoral Fellow.

Malcom Marfan: Technical Assistant.