Faculty & Research
 |
William C. Orr, Ph.D.ProfessorPh.D.: Wayne State University Postdoctoral training: |
Office: 338-DLS Tel: 214.768.4018 Fax: 214.768.3955 Email: borr@smu.edu Lab: 315-DLS/317-DLS Tel: 214.768.2065/1657 |
Research Interests
Oxidative Stress and Aging / Model Systems of Aging
My principle research focus lies in the use of
transgenic and genetic models to examine mechanisms involved in the
aging process, with emphasis on testing the Oxidative Stress Hypothesis
of Aging. There are three
on-going projects in our laboratory.
The first of these is designed to determine the effects of an increased or a decreased ability of cells to synthesize and regenerate reduced glutathione (GSH) on the aging process in fruit flies. The motivation for this effort lies in the observation that GSH can react with a variety of free radical species and is likely to work in conjunction with superoxide dismutase to provide an important mechanism for the attenuation of oxidative stress. We have generated transgenic flies over-expressing glutamate cysteine ligase and have achieved significant longevity effects (up to 50%) in a long-lived background. In continuing work we are attempting to identify “pace-maker” tissues and temporal windows where longevity effects are conferred and we are determining interactions with other pathways that have been implicated in the aging process.
In a second study we have set out to elucidate the
potential role of the thioredoxin peroxidases on oxidative stress, aging
and immunity in Drosophila.
The thioredoxin peroxidases represent a group of recently identified
components of the antioxidative network, which reduce H2O2
and organic peroxides using thioredoxin as an electron source and do so
in very specific sub-cellular compartments.
Analysis of this gene family has allowed us to reveal elements of
both antioxidant function and redox regulation related to longevity and
innate immunity.
We have also initiated a study in collaboration with Raj Sohal (USC) designed to reduce mitochondrial superoxide generation by manipulation of cytochrome c oxidase (COX) activity in transgenic flies. Various COX subunit components likely to be limiting for superoxide generation have been identified and we have begun to generate key mutant and transgenic lines.
Selected Publications
Radyuk, S.N., Rebrin, I., Klichko, V.I., Sohal, B.H., Michalak, K.,
Benes, J., Sohal, R.S. and Orr, W.C. (2010)
Mitochondrial peroxiredoxins are critical for the maintenance of
redox state and the survival of adult
Drosophila.
Free Radic. Biol. Med.
49(12),
1892-1902.
Radyuk, S. N., Michalak, K., Klichko, V. I., Benes, J. and Orr, W. C.
(2010) Peroxiredoxin 5
modulates immune response in Drosophila.
Biochim. et Biophys. Acta
1800(11),
1153-1163.
Ren, J.-C., Rebrin, I.,
Klichko, V., Orr, W.C. and Sohal R.S. (2010)
Cytochrome c oxidase loses catalytic activity and structural integrity
during the aging process in
Drosophila melanogaster.
Biochem. Biophys. Res. Commun.
401(1),
64-68.
Radyuk, S. N., Michalak, K., Klichko, V. I., Benes, J., Rebrin, I.,
Sohal, R. S. and Orr, W. C.
(2009) Peroxiredoxin 5
confers protection against oxidative stress and apoptosis and also
promotes longevity in
Drosophila. Biochem.
J.
419(2),
437-445.
Radyuk, S. N., Rebrin, I., Luchak, J. M., Michalak, K., Klichko, V. I.,
Sohal, R. S., and Orr, W. C.
(2009) The catalytic subunit
of Drosophila glutamate-cysteine
ligase is a nucleocytoplasmic shuttling protein.
J. Biol. Chem.
284, 2266-2274.
Legan, S. K.,
Rebrin, I., Mockett, R. J., Radyuk, S. N., Klichko, V. I., Sohal, R. S.,
and Orr, W. C. (2008)
Overexpression of glucose-6-phosphate dehydrogenase extends the
life span of Drosophila melanogaster.
J. Biol. Chem.
283(47),
32492-32499.
Sohal, R. S., Toroser, D., Brégere, C. Mockett, R. J. and Orr, W. C.
(2008) Age-related decrease
in expression of mitochondrial DNA encoded subunits of cytochrome c
oxidase in Drosophila
melanogaster. Mech
Ageing Dev.
129(9),
558-561.
Mockett, R. J., Sohal, R. S., and Orr, W. C.
The fruit fly Drosophila melanogaster:
roles of oxidative stress in the aging process of
Drosophila melanogaster.
In: Aging Medicine:
Oxidative Stress in Aging:
From Model System to Human Diseases.
S. Miwa, K.B. Beckman, and F.L. Muller, eds.
pp 111-128, Humana Press, Totowa, NJ
In Press
Michalak, K, Orr, W. C., and Radyuk, S. N.
(2008) Drosophila peroxiredoxin 5 is the second gene in a
dicistronic operon.
Biochem. Biophys. Res. Commun
368(2),
273-278.
Anderson, P. R., Kirby, K., Orr, W. C., Hilliker, A. J., and Phillips,
J. P. (2008)
Hydrogen peroxide scavenging rescues frataxin deficiency in a
Drosophila model of
Friedreich’s ataxia.
Proc. Natl. Acad. Sci.
USA
105,
611-616.
Toroser, D., Orr, W.C. and Sohal, R.S.
(2007) Carbonylation
of mitochondrial proteins in Drosophila melanogaster during aging.
Biochem. Biophys. Res. Commun.
Epub ahead of print.
Radyuk, S.N., Michalak, K, Rebrin, I., Sohal, R.S. and
Orr, W.C. (2006) Effects of ectopic expression of Drosophila DNA
glycosylases dOgg1 and RpS3 in mitochondria.
Free Radic. Biol. Biol. Med.
41(5), 757-764.
Toroser, D., Yarian, C.S., Orr, W.C. and Sohal, R.S.
(2006) Mechanisms of gamma-glutamylcysteine ligase regulation.
Biochim Biophys Acta
1760 (2), 233-244.
Bayne, A.C., R.J.
Mockett, W.C. Orr, and R.S. Sohal. (2005) Enhanced catabolism of
mitochondrial superoxide/hydrogen peroxide and aging in transgenic
Drosophila. Biochem J., 391 (Pt 2), 277-284.
Ferguson, M., R.J. Mockett, Y. Shen, W.C. Orr, and
R.S. Sohal. (2005) Age-associated decline in mitochondrial respiration
and electron transport in Drosophila melanogaster. Biochem J 390:
501-11.
Orr, W.C., S.N. Radyuk, L. Prabhudesai, D. Toroser,
J.J. Benes, J.M. Luchak, R.J. Mockett, I. Rebrin, J.G. Hubbard, and R.S.
Sohal. (2005) Overexpression of glutamate-cysteine ligase extends life
span in Drosophila melanogaster. J Biol Chem. 280 (45),
37331-37338.
Cooper, T.M., Mockett, R.J., Sohal, B.H., Sohal, R.S.
and Orr, W.C. (2004) Effect of caloric restriction on life
span of the housefly, Musca domestica. FASEB J. 18,
1591-1593.
Rebrin, I., Bayne, A.-C.V., Mockett, R.J., Orr, W.C.
and Sohal, R.S. (2004) Free amino thiols, glutathione redox
state and protein mixed disulfides in aging Drosophila melanogaster.
Biochem. J. 382, 131-136.
Radyuk, S.N., Klichko, V.I. and Orr, W.C. (2004)
Profiling Cu,Zn-superoxide dismutase in Drosophila melanogaster -
a critical regulatory role for intron/exon sequence within the coding
domain. Gene. 328, 37-48.
Klichko, V.I., Radyuk, S.N. and Orr, W.C. (2004)
Profiling catalase gene expression in Drosophila melanogaster during
development and aging. Archives of Insect Biochemistry and
Physiology. 56, 34-50.
Orr, W.C., Mockett, R.J., Benes, J.J. and Sohal, R.S.
(2003) Effects of copper-zinc and manganese superoxide dismutases,
catalase, and thioredoxin reductase genes on longevity in Drosophila
melanogaster. J. Biol. Chem. 278(29),
26418-26422.
Radyuk, S.N., Sohal, R.S. and Orr, W.C. (2003)
Thioredoxin peroxidases can foster cytoprotection or cell death in
response to different stressors-a study of thioredoxin peroxidase under-
and over-expression in Drosophila cells. Biochem. J.
371, 743-752.
Orr, W.C. and Sohal, R.S. (2003) Does overexpression
of Cu,Zn-SOD extend life span in Drosophila melanogaster?
Exper. Gerontol. 38(3), 227-230.
Mockett, R.J., Radyuk, S.N., Benes, J.J., Orr, W.C.
and Sohal, R.S. (2003) Phenotypic effects of familial
amyotrophic lateral sclerosis mutant SOD alleles in transgenic
Drosophila. Proc. Natl. Acad. Sci. USA. 100(1),
301-306.
Mockett, R.J., Bayne, A-C.V., Kwong, L.K., Orr, W.C.
and Sohal, R.S. (2003) Ectopic Expression of Catalase in
Drosophila Mitochondria Increases Stress Resistance but not Longevity.
Free Radic. Biol. Med. 34(2), 207-217.
Sohal, R.S., Mockett, R.J. and Orr, W.C. (2002)
Mechanisms of aging: an appraisal of the oxidative stress
hypothesis. Free Radic. Biol. Med. 33(5),
575-586.
Mockett, R.J., Orr, W.C., and Sohal, R.S (2002)
Overexpression of Cu,ZnSOD and MnSOD in transgenic Drosophila.
Methods Enzymol. 349, 213-20.
Radyuk, S.N., Klichko, V.I., Spinola, B., Sohal, R.S.,
and Orr, W.C. (2001) The peroxiredoxin gene family in
Drosophila melanogaster. Free Radic. Biol. Med. 31(9),
1090-1100.
Das, N., Levine, R.L., Orr, W.C. and Sohal, R.S.
(2001) Selectivity of protein oxidative damage during aging in
Drosophila melanogaster. Biochem. J. 360,
209-216.
Mockett, R.J., Orr, W.C., Rahmandar, J.J., Sohal, B.H.
and Sohal, R.S. (2001) Antioxidant status and stress
resistance in long- and short-lived lines of Drosophila melanogaster.
Exp. Geront. 36, 441-43.
Radyuk, S.N., Klichko, V.I. and Orr, W.C. (2000)
Catalase expression in Drosophila melanogaster is responsive to ecdysone
and exhibits both transcriptional and post-transcriptional regulation.
Arch. Insect Biochem. Physiol. 45, 79-93.
Kwong, L.K., Mockett, R.J., Bayne, A.-C.V., Orr, W.C.
and Sohal, R.S. (2000) Decreased mitochondrial hydrogen
peroxide release in transgenic Drosophila melanogaster expressing
intramitochondrial catalase. Arch. Biochem. Biophys.
383(2), 303-308.
Sohal, R.S., Mockett, R.J. and Orr, W.C. (2000)
Current issues concerning the role of oxidative stress in aging: a
perspective. In Results and Problems in Cell Differentiation,
Vol. 29 (The Molecular Genetics of Aging), Springer-Verlag,
Berlin, Ed. S. Hekimi, pp. 45-65.
Orr, W.C. and Sohal, R.S. (2000) Oxidative stress as a
governing factor in physiological aging. In Antioxidant and
Redox Regulation of Genes, Eds. C.K. Sen, H. Sies and P.A. Baeuerle,
pp. 517-530, Academic Press, San Diego.
Mockett, R.J., Orr, W.C., Rahmandar, J., Benes, J.J.,
Radyuk, S.N., Klichko, V.I. and Sohal, R.S. (1999) Overexpression
of Mn-containing superoxide dismutase in transgenic Drosophila
melanogaster. Arch. Biochem. Biophys. 371(2),
260—269.
Klichko, V.I., Radyuk, S.N. and Orr, W.C. (1999)
CuZn-SOD promoter-driven expression in the Drosophila central nervous
system. Neurobiol. Aging 20, 537-543.
Mockett, R.J., Sohal, R.S. and Orr, W.C. (1999)
Overexpression of glutathione reductase extends survival in transgenic
Drosophila melanogaster under hyperoxia but not normoxia. FASEB J.
13, 1733-1742.
Yan, L.-J., Orr, W.C. and Sohal, R.S. (1998)
Identification of oxidized proteins based on sodium sulfate-polyacrylamide
gel electrophoresis, immunochemical detection, isoelectric focusing and
microsequencing. Analytic. Biochem. 263. 67-71.
Sohal, R.S. and Orr, W.C. (1998) Role of oxidative
stress in senescence. Aging Clin. Exp. Res. 10,
149-151.
Sohal, R.S. and Orr, W.C. (1998) Oxidative stress may
be a causal factor in the aging process. Age 21, 37-38.
Candas, M., Sohal, R.S., Radyuk, S.N., Klichko, V.I.
and Orr, W.C. (1997) Molecular organization of the glutathione reductase
gene in Drosophila melanogaster. Arch. Biochem. Biophys. 339,
323-334.
Orr, W.C., Orr, E.C., Legan, S.K. and Sohal, R.S.
(1996) Molecular Analysis of the Drosophila catalase gene. Arch.
Biochem. Biophys. 330, 251-258.
Orr, W.C. (1996) Senescence: in search of causality.
Devel. Genet.18, 93-98.
Sohal, R.S., Agarwal, A., Agarwal, S. and Orr, W.C.
(1995) Simultaneous overexpression of copper- and zinc-containing
superoxide dismutase and catalase retards age-related oxidative damage
and increases metabolic potential in Drosophila melanogaster. J. Biol.
Chem. 270, 15671-15674.
Sohal, R.S., Sohal, B.H. and Orr, W.C. (1995)
Mitochondrial superoxide and hydrogen peroxide generation, protein
oxidative damage and longevity in different species of flies. Free Rad.
Biol. & Med. 19, 499-504.
Sohal, R.S. and Orr, W.C. (1995) Is oxidative stress a
causal factor in aging? In: Dahlem Workshop Report on Molecular
Aspects of Aging (K. Esser & G.M. Martin, eds.), pp. 109-127, John
Wylie & Sons, Ltd., Sussex.
Orr, W.C. & Sohal, R.S. (1994) Extension of life span
by overexpression of superoxide dismutase and catalase in Drosophila
melanogaster. Science 263, 1128-1130.
Sohal, R.S., Agarwal, S. & Orr, W.C. (1994) Oxidative
stress may be a causal factor in senescence. In: Oxidative Processes
and Antioxidants: Their Relation to Nutrition and Health Outcomes,
13th Ross Research Conference on Medical Issues (A. Roche, ed.), pp.
6-10, Ross Laboratories, Columbus, Ohio.
Sohal, R.S., Agarwal, S., Dubey, A. & Orr, W.C. (1993)
Protein oxidative damage is associated with life expectancy of
houseflies. Proc. Natl. Acad. Sci. USA 90, 7255-7259.
Orr, W.C. & Sohal, R.S. (1993) Effects of
overexpression of Cu-Zn superoxide dismutase on life span and response
to oxidative stress in Drosophila melanogaster. Arch. Biochem. Biophys.
301, 34-40.
Sohal, R.S. & Orr, W.C. Oxidative stress and aging.
In: Proceedings of the 8th International Colloquium "Biologie
Prospective." 1993. Paris: John Libbey Eurotext.
Orr, W.C., Arnold, L.A. & Sohal, R.S. (1992)
Relationship between catalase activity, life span and some parameters
associated with antioxidant defenses in Drosophila melanogaster. Mech.
Ageing Dev. 63, 287-296.
Sohal, R.S. & Orr, W.C. (1992) Relationship between
antioxidants, prooxidants, and the aging process. Ann. N.Y. Acad. Sci.
663, 74-84.
Huang, R.Y. & Orr, W.C. (1992) Broad-complex function
during oogenesis in Drosophila. Dev. Gen. 13, 277-288.
Orr, W.C. & Sohal, R.S. (1992) The effects of catalase
gene overexpression on life span and resistance to oxidative stress in
transgenic Drosophila melanogaster. Arch. Biochem. Biophys. 297, 35-41.
Orr, E.C., Bewley, G.C. & Orr, W.C. (1990) cDNA and
deduced amino acid sequence of Drosophila catalase. Nucl. Acids Res. 18,
3663.
Sohal, R.S., Arnold, L. & Orr, W.C. (1990) Effect of
age on superoxide dismutase, catalase, glutathione reductase, inorganic
peroxides, TBA-reactive material, GSH/GSSG, NADPH/NADP+ and NADH/NAD+ in
Drosophila melanogaster. Mech. Ageing Dev. 56, 223-235.
Mackay, W.J., Orr, W.C. & Bewley, G.C. Genetic and
molecular analysis of antioxidant enzymes in Drosophila melanogaster: A
correlation between catalase activity levels, life span, and spontaneous
mutation rate. In: Molecular Biology of Aging: UCLA Symposium on
Molecular and Cellular Biology (eds. Clegg, M. & O'Brien, S.), Vol.
123, pp. 157-170, Alan R. Liss, New York, 1990.
Orr, W.C., Galanopoulos, V.K., Romano, C. & Kafatos,
F.C. (1989) A female sterile screen of the Drosophila melanogaster X
chromosome using hybrid dysgenesis: Identification and characterization
of egg morphology mutants. Genetics 122, 847-858.
Galanopoulos, V.K., Orr, W.C., Szabad, J. & Kafatos,
F.C. (1989) Genetic analysis of chorion formation in Drosophila
melanogaster. I. The effects of one somatic-specific and seven germ-line
specific mutations. Dev. Genet. 10, 87-97.
Kafatos, F.C., Delidakis, C., Orr, W.C., Thireos, G.,
Komitopoulou, K. & Wong, Y.-C. Studies on the developmentally regulated
amplification and expression of Drosophila chorion genes. In:
Molecular Developmental Biology (ed. Bogorat, L.), pp. 85-101, Alan
R. Liss, New York, 1985.
Kafatos, F.C., Orr, W.C. & Delidakis, C. (1985)
Developmentally regulated gene amplification. TIG 1,
301-305.
Orr, W., Komitopoulou, K. & Kafatos, F.C. (1984)
Mutants suppressing in trans chorion gene amplification in Drosophila.
Proc. Natl. Acad. Sci. USA 81, 3773-3777.
Timberlake, W.E. & Orr, W.C. Steroid hormone
regulation of sexual reproduction in Achlya. In: Biological
Regulation and Development (ed. Yamamoto, K.), Vol. IIIB, pp.
255-283, Plenum Press, New York, 1984.
Orr, W.C. & Timberlake, W.E. (1982) Clustering of
spore-specific genes in Aspergillus nidulans. Proc. Natl. Acad. Sci. USA
79, 5976-5980.
Zimmerman, C., Orr, W.C., Leclerc, R.F., Barnard, E.C.
& Timberlake, W.E. (1980) Molecular cloning and selection of genes
regulated in Aspergillus development. Cell 21, 709-715.
Rozek, C.E., Orr, W.C. & Timberlake, W.E. (1978)
Diversity and abundance of polyadenylated RNA from Achlya ambisexualis.
Biochemistry 17, 716-722.
Support
Current Funding from the National Institute of Aging
| “Glutathione, Oxidative Stress
and Aging” Direct Costs: $ 205,000 per year, Currently one year no cost extension |
4/1/06 – 3/31/11 |
“Cellular Aging and Oxygen Free Radicals” Sub-contract: $60,000 Direct Costs per year |
4/1/07 – 3/31/12 |
|
“Peroxiredoxins, Immune Signaling and Aging" Direct Costs: $225,000 per year | 7/1/02 – 6/30/08 |
Education
| 1972 | B.A. French Literature, Wayne State University |
| 1982 | Ph.D. Biology / Biochemistry, Wayne State University |
| 1982-1985 | Post-doc, Molecular Biology of Drosophila, Harvard University (with Prof. F. C. Kafatos) |
Professional Experience
| 1986-1992 | Assistant Professor, Southern Methodist University |
| 1992-1998 | Associate Professor, Southern Methodist University |
| 1998-present | Professor, Southern Methodist University |
