Mechanisms underlying Notch function in hypoxia

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Project Summary/Abstract Hypoxia (oxygen (O2) deprivation) is a critical pathological factor that often leads to morbidity and mortality in the USA and world-wide. To date, strategies to treat or prevent O2 deprivation-induced injury is very limited. Thus, understanding the mechanisms regulating tolerance or susceptibility to O2 deprivation is crucial for developing effective therapeutic strategies. We and others have demonstrated that Notch signaling plays an important role in regulating the cellular and molecular mechanisms underlying susceptibility or tolerance to hypoxic stress. Our preliminary studies have shown that a) Notch signaling plays a critical role in regulating hypoxia tolerance, i.e., D. melanogaster carrying Notch loss-of-function alleles are “super-sensitive” to low O2, and, in contrast, flies carrying gain-of-function alleles are remarkably resistant; b) neuronal- or glial- specific activation of Notch rescues naïve flies from a lethal concentration of O2 deprivation; and c) Notch signaling is an evolutionarily conserved mechanism regulating adaptation to low O2 environments not only in Drosophila but also in humans. In addition, various studies have also shown that Notch activity is critical in preventing cardiac injury and regulating repair and regeneration after myocardial infarction. However, the molecular mechanisms underlying the role of Notch in regulating hypoxia response are not well understood. In the current application, we will identify genetic modifiers or effectors to determine the Notch downstream mechanisms that regulate cell survival under O2 deprivation in neuronal and glial cells. We chose D. melanogaster to perform such studies since we have considerable experience and data using this genetic model, and because it is a great model to dissect mechanisms. Based on our genomic work on human dwellers at high altitude, we have recently discovered a group of evolutionarily conserved genes that regulate hypoxia adaptation in both humans and Drosophila. Previous studies have shown that some of these genes (e.g., FGFR and HES1) interact and regulate/mediate Notch signaling. We will use these conserved genes to probe their role in regulating Notch-conferred hypoxia tolerance. Since these genes are highly conserved from flies to humans, the likelihood of these studies for translational and clinical applications becomes much higher. Our Specific Aims are: 1) to identify genetic modifiers that regulate Notch-conferred tolerance to O2 deprivation; and 2) to determine Notch-mediated transcriptional mechanisms mediating Notch function in hypoxia tolerance in specific neuronal and glial cells. Our goal is to identify novel mechanisms underlying Notch-conferred hypoxia tolerance that would lead to targets and strategies for better treatment or prevention.