Mammalian genome encodes tens of thousands of long noncoding RNAs (lncRNAs) which are emerging as important regulators of transcription and translation. Any perturbation in the levels and function of lncRNAs can be expected to promote pathological changes. We recently showed that transient focal cerebral ischemia (stroke) in adult rodents rapidly changes the cerebral expression profiles of lncRNAs. We further show that post-ischemic brain damage and neurological dysfunction can be mitigated significantly by inhibiting an lncRNA called FosDT that was observed to be induced after stroke. Due to their functional importance as epigenetic modulators of transcription, lncRNAs has a tremendous potential to be developed as stroke therapies. Hence, we currently propose testing the efficacy of inhibiting FosDT in rodent stroke models. We hypothesize that ?FosDT is a novel therapeutic target to protect brain after stroke.? This is the first study to our knowledge to comprehensively test the significance of an lncRNA in protecting the brain after stroke. Recent guidelines suggest that stroke therapeutic development should follow the criteria suggested by the STAIR (Stroke Treatment Academic Industry Roundtable) consortium. Hence, we will incorporate many of those recommendations in the present FosDT therapeutic testing.
Aim 1 is to test the dose and window of opportunity after stroke for FosDT therapy as a function of sex and age.
Aim 2 is to test post-stroke FosDT therapy as a function of type of ischemia, route of administration, and systemic toxicity.
Aim 3 will evaluate the efficacy of post-ischemic FosDT therapy as a function of species and diabetes (a comorbid condition) and to identify if this therapy influences the post-ischemic pathophysiologic mechanisms.
Aim 4 will evaluate the mechanisms that are upstream and downstream of FosDT in ischemic brain. Overall, this is the first systematic study to test the therapeutic potential of targeting an lncRNA to protect brain after stroke.
Finding new therapies is a priority to prevent post-stroke brain damage and to promote neurological recovery. It is important to conduct preclinical testing in young as well as aged animals of both sexes, and further in animals with comorbid conditions. In this proposal we wish to test if inhibiting a long noncoding RNA (lncRNA) promotes neuroprotection after stroke. We will incorporate many combinations and permutations like age, sex, comorbid conditions, toxicity, stroke type and species to test the lncRNA therapy in rodent stroke models. The long-term goal is to find new targets that are amenable for therapy to prevent brain damage after stroke.
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