Stroke is a leading cause of high mortality and long-term disability in the United States. Stroke is associated with the over-production of reactive oxygen and nitrogen species, which cause protein misfolding and aggregation. However, the role of aberrant protein clearance on the outcome of ischemic stroke remains far from being understood. Ubiquilin (Ubqln) is a ubiquitin-like protein that inhibits hypoxia-, nutrient starvatin- and protein misfolding-induced cell death. To understand the role of Ubqln in neuronal repair following ischemic stroke, we recently generated Ubqln transgenic and conditional knock-out mouse models and with the animals, we have found that overexpression of Ubqln protects neurons against oxidative stress and ischemia-caused brain injury while knockout of the gene exacerbates cerebral ischemia-caused neuronal damage and delays functional recovery. Although these observations confirm that Ubqln is a therapeutic target, transgenic manipulation-caused overexpression of Ubqln occurs prior to the event of ischemic stroke and it remains unknown whether delayed Ubqln overexpression in post-ischemic brains is still beneficial. In this revised proposal, we hypothesize that delayed elevation of Ubqln, within a clinically relevant time window following ischemic strok, reduces neuronal injury and enhances animal functional recovery. To test this hypothesis, the following specific aims will be pursued: (1) To determine whether elevation of Ubqln level in post-ischemic brains is neuroprotective in mice, (2) To identify the compounds that can upregulate Ublqn protein expression and validate their therapeutic effect in stroke mice, and (3) To identify the mechanisms underlying Ubqln-induced neuroprotection in ischemic stroke.
Stroke is a leading cause of high mortality and long-term disability in the United States. Stroke is associated with excessive production of damaged proteins but it remains unclear about the consequence of this event on nerve cell recovery following stroke. In this project, we propose to study whether manipulation of the expression of ubiquilin, a protein that facilitates removal of aberrant proteins, can cause any beneficial effect on the survival of nerve cells in stroke mouse models.
