Distinguished Professor and Chair , Department of Pediatrics; Professor of Neurosciences
M.D., American University of Beirut in Lebanon
Hypoxia, Ischemic Brain Injury, Notch and Wnt signalling
The overall interest of Dr. Haddad's laboratory is the effect of low oxygen or hypoxia on cell function and development. Mammalian tissues are extremely sensitive to the stress of hypoxia and can only survive for relatively short periods of time. The Haddad lab is interested in the molecular mechanisms that underlie susceptibility to injury under these conditions, especially in nerve cells and glia. To examine the susceptibility of sensitive tissues to low oxygen, mice are studied with the use of electrophysiological, molecular biological and genetic techniques.
A strong component of Dr. Haddad's research is the use of an invertebrate model, the fruit fly Drosophila melanogaster. A number of years ago, the Haddad lab has discovered that the fruit fly is very tolerant to low oxygen conditions and we are therefore taking advantage of such well studied organism to investigate its genetic endowment to better understand how fruit flies survive extreme oxygen conditions. Using a variety of screens and mutational analysis, the Haddad lab has been able to dissect the genetic basis of tolerance of fruit flies to low oxygen. In addition, they have recently generated a D. melanogaster strain that lives perpetually in an extremely low-oxygen environment (4% O2, an oxygen level that is equivalent to about 4,000 m above Mt. Everest) through laboratory selection pressure using a continuing reduction of O2 over many generations. This phenotype is genetically stable as extreme hypoxia tolerance is an inherited trait in these hypoxia-selected flies. Gene expression profiling showed striking differences between tolerant and naïve flies, in larvae and adults, both quantitatively and qualitatively. Furthermore, we have utilized this same experimental selection strategy to obtain a D. melanogaster strain that is now extremely tolerant to oxidant stress and is now living at 95% O2!! Presently, the Haddad lab is dissecting the role of a number of genes and genetic pathways in hypoxia or oxidant tolerance/susceptibility in Drosophila melanogaster as well as in humans who have lived for hundreds/thousands of years at high altitudes!
1: Haddad GG. Does the brain gain back energy during sleep? But what does it
mean? Sleep. 2011 Jul 1;34(7):835-6; author reply 841-3. PubMed PMID: 21731130;
PubMed Central PMCID: PMC3119555.
2: Felfly H, Xue J, Zambon AC, Muotri A, Zhou D, Haddad GG. Identification of a
neuronal gene expression signature: Role of cell-cycle arrest in murine neuronal
differentiation in vitro. Am J Physiol Regul Integr Comp Physiol. 2011 Jun 15.
[Epub ahead of print] PubMed PMID: 21677276.
3: Azad P, Ryu J, Haddad GG. Distinct role of Hsp70 in Drosophila hemocytes
during severe hypoxia. Free Radic Biol Med. 2011 Jul 15;51(2):530-8. Epub 2011
May 13. PubMed PMID: 21616137; PubMed Central PMCID: PMC3138732.
4: Zhao HW, Haddad GG. Review: Hypoxic and oxidative stress resistance in
Drosophila melanogaster. Placenta. 2011 Mar;32 Suppl 2:S104-8. Review. PubMed
PMID: 21353099; PubMed Central PMCID: PMC3073591.
5: Zhou D, Udpa N, Gersten M, Visk DW, Bashir A, Xue J, Frazer KA, Posakony JW,
Subramaniam S, Bafna V, Haddad GG. Experimental selection of hypoxia-tolerant
Drosophila melanogaster. Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2349-54.
Epub 2011 Jan 24. PubMed PMID: 21262834; PubMed Central PMCID: PMC3038716.
6: Zhao HW, Zhou D, Haddad GG. Antimicrobial peptides increase tolerance to
oxidant stress in Drosophila melanogaster. J Biol Chem. 2011 Feb
25;286(8):6211-8. Epub 2010 Dec 9. PubMed PMID: 21148307; PubMed Central PMCID:
7: Harrison JF, Haddad GG. Effects of oxygen on growth and size: synthesis of
molecular, organismal, and evolutionary studies with Drosophila melanogaster.
Annu Rev Physiol. 2011 Mar 17;73:95-113. Review. PubMed PMID: 20936942.
8: Zhao HW, Zhou D, Nizet V, Haddad GG. Experimental selection for Drosophila
survival in extremely high O2 environments. PLoS One. 2010 Jul 23;5(7):e11701.
PubMed PMID: 20668515; PubMed Central PMCID: PMC2909141.
9: Felfly H, Muotri A, Yao H, Haddad GG. Hematopoietic stem cell transplantation
protects mice from lethal stroke. Exp Neurol. 2010 Oct;225(2):284-93. Epub 2010
Jun 12. PubMed PMID: 20547154; PubMed Central PMCID: PMC2963425.
10: Xue J, Mraiche F, Zhou D, Karmazyn M, Oka T, Fliegel L, Haddad GG. Elevated
myocardial Na+/H+ exchanger isoform 1 activity elicits gene expression that leads
to cardiac hypertrophy. Physiol Genomics. 2010 Aug;42(3):374-83. Epub 2010 May
11. PubMed PMID: 20460605; PubMed Central PMCID: PMC2929882.