Stroke is the third leading cause of death in the USA and the leading cause of long- term disability. Unfortunately, there are few available pharmacotherapies capable of limiting damage following a stroke. For this reason, novel targets for post-stroke therapies are desperately needed. We recently identified the secreted factor prosaposin and its active fragment prosaptide as ligands for the brain-expressed G protein-coupled receptors GPR37 and GPR37L1. Interestingly, prosaptide has been extensively studied for two decades as a peptide that improves recovery in rodent models of stroke. However, it is not known at present if prosaptide exerts these protective effects in vivo via stimulation of GPR37 and/or GPR37L1. Moreover, nothing is known about the signaling pathways downstream of GPR37 and GPR37L1 that might be relevant to the protective actions of prosaposin and prosaptide. In this project, we will study the protective actions of prosaptide on primary cortical astrocytes, a cell type that expresses both GPR37 & GPR37L1, and elucidate the signaling pathways downstream of these receptors that mediate the pro-survival effects of prosaptide treatment following oxygen/glucose deprivation. We will also seek to understand the mechanisms by which the protective signaling pathways downstream of GPR37 & GPR37L1 are regulated, since nothing is currently known about this topic. Furthermore, we will perform parallel studies in vivo in which we will study damage induced by focal cerebral ischemia in wild- type mice as well as mice lacking expression of GPR37 and/or GPR37L1 in order to assess the importance of these receptors and their downstream signaling pathways in mitigating damage following a stroke and mediating the protective actions of prosaptide. These studies will provide insights into the potential utility of GPR37 & GPR37L1 as novel targets for the treatment of stroke and also shed light on the signaling pathways downstream of these receptors that are relevant to their protective effects.
Stroke is the third leading cause of death in the USA and the leading cause of long- term disability. Unfortunately, there are few available pharmacotherapies capable of limiting damage following a stroke. For this reason, novel targets for post-stroke therapies are desperately needed. In this project, we will study the brain-expressed receptors GPR37 and GPR37L1, which are activated by a ligand known to exert protective effects following stroke. In both cultured cells and a mouse model of stroke in vivo, we will assess the protective actions of these receptors and the relevant downstream signaling pathways. These studies will provide insights into the potential utility of GPR37 & GPR37L1 as novel targets for the treatment of stroke and also shed light on the signaling pathways downstream of these receptors that mediate their protective effects.
| Giddens, Michelle M; Wong, Jennifer C; Schroeder, Jason P et al. (2017) GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant. Neurobiol Dis 106:181-190 |
| Smith, Brilee M; Giddens, Michelle M; Neil, Jessica et al. (2017) Mice lacking Gpr37 exhibit decreased expression of the myelin-associated glycoprotein MAG and increased susceptibility to demyelination. Neuroscience 358:49-57 |
| Meyer, Rebecca C; Giddens, Michelle M; Coleman, Brilee M et al. (2014) The protective role of prosaposin and its receptors in the nervous system. Brain Res 1585:1-12 |
