Gordon P. Meares, PhD

Associate Professor

Organization:

West Virginia University School of Medicine

Department:

Rockefeller Neuroscience Institute (SOM)

Classification:

Faculty

• PhD, University of Alabama at Birmingham, 2007
• BS, Auburn University, 2001

[2017]

Member: 
Center for Neuroscience 
Center for Basic and Translational Stroke Research 

The research in my laboratory is focused on neuroimmunology. We are working to understanding the cellular and molecular mechanisms regulating inflammation in the central nervous system (CNS) and the role of inflammation in neurological diseases. We are interested in the inflammatory reaction in glial cells (astrocytes and microglia) in response to metabolic perturbations and injury; and the impact that glial cells have on other cell types present in the CNS.  

The Meares lab is currently accepting students. 

Current Research:
Multiple Sclerosis (MS), a chronic and incurable autoimmune and neurodegenerative disease in which the immune system aberrantly attacks and causes damage to the brain and spinal cord leading to impaired motor and cognitive functions. Inflammation in the CNS is a central pathological feature in MS. In order to discover new therapies aimed at preventing and/or reversing the devastating effects of MS, as well as other neurological diseases it is essential to define the regulatory mechanisms controlling inflammation in the CNS. Recent evidence suggests that AMP-activated protein kinase (AMPK) has anti-inflammatory properties. AMPK is inhibited during experimental autoimmune encephalomyelitis (EAE), a model commonly used to study Multiple Sclerosis. If this inhibition is reversed by pharmacological activation of AMPK, disease is attenuated. However, mechanisms through which AMPK controls inflammation in the CNS and the cell types involved have not been examined. The goal of this National Multiple Sclerosis Society (NMSS)-funded project is to determine the role of AMPK and the upstream kinase LKB1 in the regulation of inflammatory pathways in glial cells. We are using conditional knockout mice together with the mouse model of EAE and primary glial cell cultures to determine the cell-specific effects of LKB1/AMPK signaling on neuroinflammation.

Misfolded protein accumulation in the ER is present in many neurodegenerative diseases and leads to activation of the unfolded protein response (UPR). There are three main signal transducers, PERK, ATF6 and IRE1, which transmit signals from the ER to the cytosol and nucleus to elicit an adaptive stress response. Additionally, the UPR stimulates an innate immune response including acute phase cytokines such as IL-6 and chemoattractant chemokines. It is known that misfolded proteins and ER stress in vitro can be cytotoxic to neurons. However, far less is known about how ER stress influences glial cells, though glial cells display markers of ER stress in neurodegenerative diseases. We recently discovered that PERK stimulates the activation of the JAK/STAT pathway, a key pathway in inflammatory signaling. The goal of this project is to identify the cell and non-cell autonomous role of ER stress-induced inflammation in the CNS. We will also elucidate the mechanisms and role of PERK-JAK-STAT signaling. This project also utilizes cell-specific knockout mice and models of neuroinflammation.  

Inflammation is overwhelmingly beneficial. However, in many diseases, inflammation can be aberrantly sustained contributing to tissue damage and disease pathology. Extensive transcriptional reprogramming occurs during chronic neuroinflammation. Unfortunately our current knowledge of neuroinflammation lacks an integrative cellular and transcriptional understanding of how inflammatory responses are initiated, maintained and changed over time in the CNS. To begin to unravel this complex process, we are mapping the transcriptome-wide inflammatory response in glial cells in vivo. In this project we are using in vivo cell-specific genetic labeling of RNA coupled with next generation sequencing (RNA-seq) and bioinformatics to identify transcriptome wide changes in gene and microRNA expression.   

1. The Role of LKB1 and AMPK in Neuroinflammation: Multiple Sclerosis (MS), a chronic and incurable autoimmune and neurodegenerative disease in which the immune system aberrantly attacks and causes damage to the brain and spinal cord leading to impaired motor and cognitive functions. Inflammation in the CNS is a central pathological feature in MS. In order to discover new therapies aimed at preventing and/or reversing the devastating effects of MS, as well as other neurological diseases it is essential to define the regulatory mechanisms controlling inflammation in the CNS. Recent evidence suggests that AMP-activated protein kinase (AMPK) has anti-inflammatory properties. AMPK is inhibited during experimental autoimmune encephalomyelitis (EAE), a model commonly used to study Multiple Sclerosis. If this inhibition is reversed by pharmacological activation of AMPK, disease is attenuated. However, mechanisms through which AMPK controls inflammation in the CNS and the cell types involved have not been examined. The goal of this National Multiple Sclerosis Society (NMSS)-funded project is to determine the role of AMPK and the upstream kinase LKB1 in the regulation of inflammatory pathways in glial cells. We are using conditional knockout mice together with the mouse model of EAE and primary glial cell cultures to determine the cell-specific effects of LKB1/AMPK signaling on neuroinflammation. 
2. Elucidation of PERK-dependent Inflammatory Signaling: Misfolded protein accumulation in the ER is present in many neurodegenerative diseases and leads to activation of the unfolded protein response (UPR). There are three main signal transducers, PERK, ATF6 and IRE1, which transmit signals from the ER to the cytosol and nucleus to elicit an adaptive stress response. Additionally, the UPR stimulates an innate immune response including acute phase cytokines such as IL-6 and chemoattractant chemokines. It is known that misfolded proteins and ER stress in vitro can be cytotoxic to neurons. However, far less is known about how ER stress influences glial cells, though glial cells display markers of ER stress in neurodegenerative diseases. We recently discovered that PERK stimulates the activation of the JAK/STAT pathway, a key pathway in inflammatory signaling. The goal of this project is to identify the cell and non-cell autonomous role of ER stress-induced inflammation in the CNS. We will also elucidate the mechanisms and role of PERK-JAK-STAT signaling. This project also utilizes cell-specific knockout mice and models of neuroinflammation. 
3. Mapping the Transcriptome-wide Neuroinflammatory Response: Inflammation is overwhelmingly beneficial. However, in many diseases, inflammation can be aberrantly sustained contributing to tissue damage and disease pathology. Extensive transcriptional reprogramming occurs during chronic neuroinflammation. Unfortunately our current knowledge of neuroinflammation lacks an integrative cellular and transcriptional understanding of how inflammatory responses are initiated, maintained and changed over time in the CNS. To begin to unravel this complex process, we are mapping the transcriptome-wide inflammatory response in glial cells in vivo. In this project we are using in vivo cell-specific genetic labeling of RNA coupled with next generation sequencing (RNA-seq) and bioinformatics to identify transcriptome wide changes in gene and microRNA expression.