Gabriel G. HADDAD
Distinguished Professor, Pediatrics & Neuroscience, USA

The overall interest of Dr. Haddad's laboratory is the effect of hypoxia (and hypercapnia) 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. In particular, the laboratory is interested in the genetic and molecular mechanisms of cell death and cell survival in oxygen deprivation as well as the mechanisms of tolerance and susceptibility to low oxygen environment, especially in nerve cells and glia. To examine the susceptibility of sensitive tissues to low oxygen, we have resorted to the study of mice and the use of molecular biologic and genetic techniques. Previously, we have investigated the role of transporters, channels, and exchangers (in mitochondria or plasma membranes) in hypoxia, the interactions between innate immunity and hypoxia, and the role of CO2 in affecting excitability and gene expression. We have demonstrated that Toll-like receptor 2 is important in the CNS during hypoxia, and that certain membrane proteins such as sarcospan, BK channels, Slack, Na/H exchangers, as well as arachidonic acid play a crucial role in cell death/cell survival during hypoxia/ischemia. Additionally, we have shown that intermittent and constant hypoxia have very different effects on CNS function and that some aspects are irreversibly altered when the young brain is stressed, especially with hypoxia, such as dysmyelination.

 

There are also organisms, however, that are capable themselves of surviving prolonged and severe levels of low oxygen. Cells from these organisms can adapt and survive in severe oxygen conditions. We are therefore interested also in the ability of such cells and tissues to tolerate these hypoxic insults. A component of Dr. Haddad's research is the use of an invertebrate model, Drosophila melanogaster. We have discovered in the past 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. We are using a variety of screens and mutational analysis to dissect the genetic basis of tolerance of fruit flies to low oxygen. In addition, we have recently generated a fruit fly strain that lives perpetually in an extremely low-oxygen environment (3.5% O2, an oxygen level that is equivalent to about 4,000 m above Mt. Everest) through laboratory selection 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. We are dissecting the role of several genes and genetic pathways in hypoxia tolerance in Drosophila melanogaster. We have now extended this work to human high altitude dwellers.

 

In the past few years and in collaboration with Drs. A. Malhotra, R. Knight and P. Dorrestein, Dr. Haddad has started to focus on OSA (intermittent hypoxia/hypercapnia) and changes in the microbiome. His lab had developed a model in ApoE and Ldlr mice to investigate the relation between gaseous changes and atherosclerosis. At present these studies dissect the role of the microbiome in OSA-induced atherosclerosis. 

 

As Chair of the Department of Pediatrics at UC San Diego, best known for cutting-edge basic and translation research, and Physician-in-Chief at Rady’s Children’s Hospital, best known for world-class patient care, Dr. Haddad focuses much of his effort on bridging scientific discoveries and clinical care. A consistent theme throughout his career has been a commitment to improving children’s health through research, and       to training other physicians to do the same. Many physicians have completed postdoctoral training in his laboratory and gone on to set up their own laboratories, where they continue to make medically important biological discoveries.