Thesis/Defense Presentations

Thomas Delgado, MS - PhD Candidate

Following injury, astrocytes take on reactive phenotypes that grade from neurotoxic to neuroprotective, which impact subsequent neuronal recovery processes, such as axonal regeneration. Little is known about the contextual requirements and molecular inflection points that underlie these graded responses. Accumulating data from our lab suggests that one of these inflection points is transglutaminase 2 (TG2). TG2 is a functionally versatile protein— a biological “swiss-army knife”— that has well-established roles across cellular compartments, including the nucleus where it can enzymatically modify and serve as a protein scaffold with chromatin-regulatory proteins. Previous findings by our lab show that TG2 regulates gene expression changes in astrocytes in in vitro and in vivo mouse models of CNS injury and influences overall pathological outcomes. Our lab has shown that deletion of TG2 improves astrocyte protection of neurons from oxygen-glucose deprivation (OGD) in a cell co-culture model and improves the ability of astrocytes to promote neurite outgrowth of co-cultured neurons on an injury-relevant, growth-inhibitory matrix. Further, astrocyte-specific TG2 deletion improves motor function recovery in a mouse spinal cord injury model consistent with attenuated astrocyte pathology around the injury site. Our recent data suggest that these functional differences in astrocytes are associated with proteomic and metabolomic signatures indicative of greater metabolic flexibility under stress.

We hypothesize that astrocytic TG2 acts as a transcriptional co-regulator that restricts stress-responsive metabolism, thereby limiting astrocyte-mediated support of axonal regeneration and resolution of pathological oxidative stress following CNS injury. To interrogate this hypothesis in vivo, we used a weight-drop model of repetitive, mild traumatic brain injury (rmTBI) for wild type and global TG2 knockout mice. mTBI is one of the most common forms of CNS injury and is characterized by diffuse axonal injury and persistent metabolic dysfunction and oxidative stress. This model allowed us to monitor pathological progression through multiparametric MRI as well as analyze and integrate proteomic, metabolomic, and epigenetic changes in isolated cortical astrocytes. Twenty-eight days post-injury, TG2 knockout mice show marked attenuation of TBI pathology through functional and diffusion MRI as well as reduced astrogliosis across TBI-vulnerable brain regions through immunohistochemistry. Consistent with our hypothesis, metabolomics and proteomics of astrocytes isolated from wild type mice show an injury-induced metabolic restriction, which is attenuated in isolated TG2 knockout astrocytes. Together, these studies identify TG2 as a key molecular brake on astrocyte metabolic adaptation following CNS injury and provide a foundation for future studies using astrocyte-specific TG2 deletion and pharmacological TG2 inhibition to evaluate therapeutic potential in TBI.

 Jun 05, 2026 @ 9:00 a.m.
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