ER Stress Signaling in the CNS
Hypoxic-ischemic stress in the CNS is a potent stimulus for both gene expression and activation of the unfolded protein response originating from the endoplasmic reticulum (ER). Signals originating from receptors embedded within the ER influence protein-protein interactions between the family of bZIP transcription factors including C/EBP-beta, ATF4, and CHOP-10. It has been long recognized that the effects of ER signaling on both transcription and translation can control the balance between adaptive to pathologic transcription. However, the discrete signals that govern which of these influences dominate remain to be established.
Lung-Brain Coupling, Innate Immunity, and Neurovascular Injury
Neutrophils (PMNs) are the first cells to respond to an inflammatory stimulus and can cause direct neurotoxicity by producing reactive oxygen species, degradative enzymes, and chemokines that recruit more cells to the site of injury. PMN priming is a two-stage activation process that results in maximal degranulation and NADPH oxidase activity at the terminal site of migration. Our lab explores PMN priming and trafficking in models of focal stroke and cardiac arrest. We find that cerebral ischemia-reperfusion injury is exacerbated by systemic inflammation, consistent with observations from the clinical literature.
Drug Development for Cerebrovascular Diseases
The forces driving tissue loss after cerebral ischemia are temporally and mechanistically diverse involving cell-autonomous and non-autonomous responses. Necrosis, regulated cell death (RCD), and neuroinflammation cause tissue damage and impede functional recovery. Also, the shedding of damage-associated molecules heightens peripheral immune activation and reperfusion injury. This complexity remains a fundamental challenge to developing effective neuroprotective strategies.
Mechanisms of HIF-1⍺ Regulation in CNS Disease
Glioblastoma multiforme (GBM) is the most common primary brain malignancy in the United States and represents a range phenotypes displaying extreme heterogeneity and aggressiveness. Hypoxic gradients within the tumor microenvironment activate transcription by the master regulator hypoxia-inducible factor 1α (HIF-1α) with profound effects on tumor metabolism among other cardinal features of the disorder. The current project tests the hypothesis that the mitogen-activated protein kinase phosphatase MKP-1 plays an important role in tumorigenesis through its ability to suppress HIF-1α activity.