Cerebral ischemic injury triggers changes in various genes that mediate inflammation and cell death, as well as reorganization and repair. Identifying and exploring molecules that participate in the pathological mechanisms underlying ischemic injury will help elucidate potential therapeutic targets in the treatment of stroke. The objective of this proposal is to investigate the role of Prokineticin 2 (PK2) in cerebral ischemia. This protein was first identified in 2001 as a regulator of gastrointestinal motility. Multiple biological roles for PKs have since been discovered, including ones relevant to the central nervous system. PK genes possess multiple hypoxia responsive elements (HREs) in their promoter and their expression is inducible by hypoxia in vitro. During neurological insults such as cerebral ischemia, it is unknown whether PK2 plays a protective or deleterious role. The hypoxia-induced PK2 may be protective, in that PK2 activates Akt and MAPK pathways and protects against excitotoxicity in cerebellar cultures. However, such hypoxia-induced PK2 expression may be deleterious, given that PK2 also induces monocyte and macrophage migration and attracts inflammatory cells. No studies have investigated whether PK2 modulates ischemic outcome during cerebral ischemia. Our preliminary data showed that PK2 expression is induced in the rat striatum after middle cerebral artery occlusion (MGAO). Intriguingly, intracerebroventricular (ICV) delivery of PK2 post- ischemia resulted in an increased infarct volume, and blocking the PK2 receptor with an antagonist (PKR-A) reduced infarct volume. These pilot data suggest that PK2 could contribute to the pathological mechanisms of stroke. Here we propose to further characterize the induction profile of PK2 following MCAO, and to determine which cell type is inducing PK2. We will also complete a dose response study of PK2 on infarct volume. Furthermore, we will examine the protective time window of PK2 receptor antagonist when given post-ischemia, and whether the PK2 receptor antagonist also improves behavioral stroke outcome. The mechanism of how PK2 affects ischemic injury will also be explored.
Stroke is a major neurological insult that disrupts brain function and causes neuron death, and effective therapies are still very limited. We believe that PK2 may be an important modulator of ischemic injury, and thus a potential novel target for the treatment of stroke. ? ?
| Cheng, Michelle Y; Lee, Alex G; Culbertson, Collin et al. (2012) Prokineticin 2 is an endangering mediator of cerebral ischemic injury. Proc Natl Acad Sci U S A 109:5475-80 |
