The two main pathways of programmed cell death (PCD) are apoptosis, which is non-inflammatory, and necroptosis, which is inflammatory. Neonatal hypoxia-ischemia (HI) brain injury has an incidence of 1 to 6 per 1000 full-term births and is the third most common cause of neonatal death. Damage in this injury is primarily driven by apoptosis. Hyperglycemia, which may be caused by glucose infusion, insulin resistance, diabetes mellitus, or stress due to injury in the neonate, exacerbates HI-brain injury. We have shown that hyperglycemia induces a shift from apoptosis to necroptosis in cultured monocytes and microglia. We have also shown that hyperglycemia exacerbates neonatal HI-brain injury in vivo in a manner that depends on necroptosis concurrent with increases in necroptosis kinases and decreases in markers of apoptosis. We hypothesize that hyperglycemia promotes a shift from apoptosis to necroptosis in neurons, microglia, and infiltrating monocytes during neonatal HI-brain injury. In this context, we believe that in the inflammatory milieu of the brain, microglia and monocytes will encounter cell death agonists and undergo necroptosis leading to death of bystander neurons exacerbating the injury. We will explore the underlying mechanism of the hyperglycemic shift to necroptosis in monocytes and microglia and determine if the shift to necroptosis in monocytes and microglia leads to death of bystander neurons thereby exacerbating neonatal HI-brain injury.
In Aim 1 A we will analyze the role of mitochondrial factors in the hyperglycemic shift to necroptosis and their relation to increases in ROS during this phenomenon.
In Aim 1 B, we will explore the trafficking of cell death factors to the nucleus during the hyperglycemic shift to necroptosis as well as effects on gene expression.
In Aim 1 C we will test the hypothesis that the hyperglycemic shift from apoptosis to necroptosis in monocytes and microglia leads to bystander death of cultured neurons. As part of this aim we will determine factors responsible for bystander neuronal death and mechanisms of bystander death.
In Aim 2 we will determine the mechanism of the hyperglycemic shift from apoptosis to necroptosis during neonatal HI-brain injury in vivo.
In Aim 2 A we will analyze the role of microglia and monocytes in the hyperglycemic shift to necroptosis during neonatal HI-brain injury using MaFIA mice.
In Aim 2 B we will explore the role of bystander neuronal death in the injury via intracerebroventricular administration of myeloid vesicles. This work will reveal molecular targets for therapeutic intervention. We believe that, due to PCD shift in hyperglycemia, different therapeutic approaches will be necessary in the context of euglycemia vs. hyperglycemia.
This application is designed to investigate the mechanism of programmed cell death shift induced by hyperglycemia as it relates to blood cells in neonatal hypoxia-ischemia brain injury. It is well-established that hyperglycemia exacerbates this injury, therefore, by studying the dynamics and mechanisms of blood cell death in hyperglycemia we will determine the underlying mechanism of this exacerbation. This work will lead to a fundamental difference in therapeutic approach to this injury in euglycemic vs. hyperglycemic neonates.
|McCaig, William D; Patel, Payal S; Sosunov, Sergey A et al. (2018) Hyperglycemia potentiates a shift from apoptosis to RIP1-dependent necroptosis. Cell Death Discov 4:55|
|Rong, Yinghui; Westfall, Jennifer; Ehrbar, Dylan et al. (2018) TRAIL (CD253) Sensitizes Human Airway Epithelial Cells to Toxin-Induced Cell Death. mSphere 3:|