Kevin K. W. Wang, PhD

Andrew K. Ottens, PhD

Stanislav I. Svetlov, MD,PhD

MingCheng Liu, MD

Stephen F. Larner, PhD

 

Kevin K.W.Wang, PhD

Areas of Interest :
CNS injury, proteases, proteomics, calcium-binding proteins, biomarkers

Summary of Research Interests:

Clinical Interests
Dr. Wang’s main clinical interests include: the diagnostics and patient management of substance abuse (ecstasy, methamphetamine, chronic alcohol abuse and binge drinking), the neurotoxic consequences of substance abuse, traumatic and ischemic brain injury, as well as other major psychiatric disorders (schizophrenia, bipolar disorder, major depression, anxiety, obsessive-compulsive behavior). He hopes development of CNS disease diagnostic assays can positively impact on the objective, quantitative diagnosis of major psychiatric disorders, patient care and management, identification of injury mechanism and drug target, early assessment of treatment efficacy, reduction costs/risks of clinical trials with the use of surrogate markers as endpoints.

Research Interests And Scholarly Interests
Dr. Wang built his research career on unveiling proteolytic mechanisms involved in traumatic and ischemic brain injury. Dr. Wang is internationally recognized for his contributions to the field of CNS disorders-linked proteases and has been invited worldwide to present his research. He co-edited a book entitled “Calpain: the Pharmacology and Toxicology of a calcium-dependent protease” in 2000. His more recent research has expanded to proteomic technologies to psychiatric disorders because neuronal injury biomarkers are also highly relevant to psychiatric diseases such as substance abuse and schizophrenia. His laboratory is developing animal model for substance abuse (ecstasy (MDMA), methamphetamine and alcohol abuse). In parallel, his group is employing an integrated proteomics-based approach to discover novel biomarkers for these psychiatric diseases. These technologies include: (1) 2D gel electrophoresis-MALDI-TOF, (2) 2D-LC-MS/MS, (3) antibody (scFv)-expressing phage library panning, and (4) monoclonal antibody panel.

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Andrew K.Ottens, PhD

Areas of Interest :
Neuroproteomics, Degradomics, Proteolysis, Protein Dynamics, Brain Injury, Brain Tumor

Summary of Research Interests:
The innate complexity of the central nervous system (CNS) necessitates use of interdisciplinary approaches to unravel the complexities of the brain. Our interest is in applying bioanalytical methodologies to deciphering biological mechanisms involved in brain injury and neuronal regeneration. Assault of the brain can occur through mechanical trauma (TBI), ischemia (stroke), toxic abuse (drugs, alcohol), or age related disease (AD & PD). We utilize neuroproteomic technologies to uncover cellular changes at the protein level in response to these insults. Such changes can occur as expression differences, post-translational modifications, or proteolytic degradation. Our group is developing tools to investigate specific cases of all three, and apply them to brain injury. We have also begun engineering a clinical biomonitoring device, directly applying proteomics to human medical diagnostics. More recently we have applied neuroproteomic analysis to investigate neurite regeneration pathways influenced by growth factor stimuli. Our overall mission is to understand mechanisms of neuronal injury for diagnostic purposes and to provide direction for regeneration therapy.

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Stanislav I. Svetlov, MD/PhD

Areas of Interest:
Biomarkers of multiple organ injury/regeneration: neuromediators, cannabinoids and their receptors; Stem cell fate during injury/regeneration.

Summary of Research Interests:
I am focusing my research on the endogenous lipid neuromediators and their receptors in neural progenitor fate using in vitro techniques and in vivo models of Brain Injury.
These studies include lysolipids, endocannabinoids and their receptors and antagonists. Recently, we have discovered that lysophosphatidic acid (LPA) generated clonal neurospheres from postnatal mouse forebrain via proliferation of Sca-1 and AC133 positive primitive stem/progenitor cells in LPA receptor-dependent fashion (Stem Cells & Development, 2004 in press). LPA also regulated differentiation of these cells into cells of neuronal and glial lineages. These studies provided a new medium formulation to initiate formation and maintain growth of neurospheres in long-term cultures (US patent pending). Human neural stem cells are being investigated under this paradigm. We are also developing novel pathogenic markers of traumatic Brain Injury (TBI) based on detection of cannabinoid receptor fragments in CSF.
LPA and endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are all endogenous bioactive lipids, which act via homologues G protein-coupled receptors. Experiments are on the way to examine the potential activities of AEA and 2-AG towards neural stem cell using a model of clonal neurosphere generation. We are investigating whether AEA and 2-AG are able to induce proliferation of neural progenitors, what cells are primarily responsible for clonal activity and what is the cell differentiation profile evoked by endocannabinoids and LPA. In addition, the roles for LPA and cannabinoid receptors in neural stem cells have been investigated using (i)specific LPA and CB1 receptor antagonists, and (ii)CB1 and LPA receptor knockout mice. Most important, a number of these compounds targeting endogenous neural progenitors along with stem cell transplantation-based therapy have been considered for neuroprotection/regeneration following both TBI and stroke.

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MingCheng Liu, MD

coming soon...

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Stephen F. Larner, PhD

Areas of Interest:
Apoptosis, Autophagy, Caspases, Unfolded Protein Response (UPR), ER Stress

Summary of research interest:
Traumatic brain injury (TBI) causes progressive neuronal degeneration resulting from acute and delayed cell death in part by apoptotic inducing caspases. Programmed cell death, apoptosis, a conserved active molecular process often requires active transcription and translation of proteins for initiation of the molecular program that eradicates excess or potentially dangerous cells. Apoptosis is mediated, in part, by caspases, a 14-member family of aspartate-specific cysteine-dependent proteases. One important consequence of the loss of endoplasmic reticulum (ER) calcium homeostasis following central nervous system injury is the activation of the unfolded protein response (UPR), which determines whether cells survive or undergo apoptosis. The discovery that caspase-12 is linked to the ER and activated only upon ER perturbation suggested a new apoptotic pathway. This activation induces and activates caspase-12 by caspase-7 and calpain following excess ER stress and, it is believed, apoptotic cell death. Data from our laboratory after using the lateral controlled cortical impact model of TBI on rats suggest that caspase-12 and caspase-7 are involved in this process where caspase-7 may play a role in the activation of caspase-12 and then in turn may be activated by caspase-12. Our published data of traumatized tissues shows increased mRNA transcription and increased levels and activation of caspase-12 protein in both neurons and astrocytes. In a report that is in progress the data show the same evidences for caspase-7. These findings are the first to document the up-regulation of caspase-7 in the brain following acute injury and that caspase-7 activation could contribute to neurodegeneration. If caspase-12 is activated by caspase-7 and then in turn activates caspase-7 a feedback loop may exist between caspase-12 and caspase-7 and this may be important to understanding the neuropathological progression of the disease over time and to offer the researchers a therapeutic target for treatment. An added complexity that increases the difficulty of studying the caspase-12/caspase-7 story is the number of alternative spliced mRNAs that may exist for each caspase. Caspase-7 has been reported to have 3 isoforms. To date no one has examined the individual role of any of these three. Caspase-12 in humans has been cited to have 9 isoforms. Since apoptosis occurs following TBI in animals and humans, understanding the biochemical and molecular mechanisms of apoptotic cell death is important to finding the means to assess and treat patients with pathological TBI

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