To Investigate the Role of SPNS2 in Determining Individual Susceptibility to Hypoxic Challenge

Oxygen deprivation or hypoxic challenge, contributes significantly to the pathophysiology of many human neurodegenerative diseases. The better understanding of the fundamental molecular and genetic basis of hypoxic events might help to develop therapeutic strategies to prevent or treat certain hypoxic pathogenesis in clinic. Currently, most of the investigations in the field are focused on studying the underlying “mediators or effectors” that contribute to irreversible neuronal damage and develop drugs for that. However, since clinical experience indicated that everyone responds differently to the hypoxic insults. So it could be an interesting question to ask when facing hypoxic challenge, why some people recovered well without significant phenotypes but others might display hypersensitive phenotypes with severe traumatic damage? And if there might be any unrevealed determining factors which may modulate individual susceptibility to develop hypoxic sensitive phenotypes? Here in this proposal, based on previous literatures and our preliminary observations, we proposed that SPNS2 (Spinster homolog 2) could be a potential molecule to display such property. Basically, our proposal composed of three specific aims: First, by using a standard hypoxic rodent model (MCAO, middle cerebral artery occlusion), the individual expression level of SPNS2 will be compared between hypoxic-susceptible and resistant individuals. And then, local genetic manipulation of SPNS2 expression level by intracerebral injection of pseudotyped lenti-virus will be conducted to see if bidirectional alterations in SPNS2 level may switch individual’s hypoxic sensitivity. Second, the inducibility and functional significance of SPNS2 in the phenomenon of “physiological adaptation to hypoxia” will be tested in two distinct hypoxic adaptation animal models: low or high oxygenated living environment and hypoxic preconditioning protocols. Furthermore, by using an in vitro pharmacological screening model of SPNS2 dependent reporter cell line, we will screen for pharmacological regimens that could boost the expression of SPNS2 and test their functional significance in promoting hypoxic resistant phenotypes in vivo. Our proposal has the potential to develop a novel and valuable therapeutic strategy which may be able to reduce irreversible neurological damage in clinic by improving individual capability for resilience after hypoxic challenge.