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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. Furthermore, we have also been interested in long term hypoxia and in the adaptation of cells and tissues to this stress, in the hope that we can learn enough from the tolerant/adapted cells and tissues to be able to manipulate sensitive tissues to become more tolerant and less likely to be injured during hypoxic stress.

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. To explore the importance of hypoxia or other environmental or drug influences in early fetal brain development, we have developed in our lab a brain organoid (cortical and hindbrain) model recently. This model will help us also in understanding disease mutation on the cellular and molecular mechanisms involved in early brain development. In particular, we have focused on fetal brain development under the influence of methadone (drug abuse or use during pregnancy) as well as the effect of some genetic disorder on fetal cortical and hindbrain development.

Figure: Electrophysiological recordings of human cortical organoids show robust synaptic activity and progressive increase of intrinsic neuronal excitability.

Since there are organisms that are capable themselves of surviving prolonged and severe levels of low oxygen, these organisms can survive severe oxygen conditions. We are therefore interested also in the ability of such organisms to understand how their tissues can tolerate such severe 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 adult 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 through a laboratory selection experiment over two decades ("Darwinian" experiment) 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) 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 and are focusing on human phenotypes that are very interesting and important as these are deleterious to subjects at high altitude if they are mal-adapted.

Figure: Karzok village in Ladakh, India, in the Himalayas. At 4,570 meters above sea level, it is the highest settlement in India and one of the highest permanent human settlements in the world.

In the past few years and in collaboration with Drs. R. Knight and P. Dorrestein, we have started to focus on OSA (intermittent hypoxia/hypercapnia) and changes in the microbiome. Our 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.