Gregory A. Ordway, Ph.D.
Department of Biomedical Sciences
B.S. Pharmacy; The Ohio State University
Timothy Diperi (medical student)
Assistant Professor, Assistant Clinical Professor; Case Western Reserve University 1988-2000
1. Major depression and antidepressants
Our research on MAJOR DEPRESSION AND SUICIDE.
Major depression is a devastating disorder that affects millions of Americans each year. Sadly, over 42,000 people have died by suicide each year in the U.S. since 2014 according to the CDC. Studies have shown that most people who die by suicide suffered from depression in some form, whether having major depressive disorder or depression in association with other psychiatric disorders. A large number of studies have demonstrated brain white matter pathology in patients with depression. There is also a strong link of stress and depression to conditions of inflammation that are subsequently linked to elevated oxidative stress and free radical damage. However, the molecular and cellular consequences of stress- and depression-induced inflammation and oxidative damage in the brain are poorly understood. My laboratory is focused on elucidating the biochemical and cellular consequences of stress- and depression-associated inflammation and oxidative damage on the brain, focusing specifically on the unique cells in brain white matter. We use a variety of modern methods to investigate pathology and mechanisms underlying pathology, and focus these efforts at the cellular level by using laser capture microdissection to isolate specific types of cells from the human brain. We have access to a large collection of psychiatrically characterized human brain tissues that allow us to identify cellular pathology in the brains of donors with specific psychiatric diagnoses and/or who have died by suicide, using brain tissues from psychiatrically normal donors who died from natural causes as controls. We are also initiating laboratory animal studies to investigate specific mechanisms by which psychological stress and depression induce white matter cell pathology in the brain. White matter damage in depression is likely to contribute to abnormal axonal conduction of neural information between brain regions and could be a major contributor to the psychopathology of depression. Developing treatments to subvert this pathology in depression could reduce morbidity and mortality associated with this typically debilitating disorder.
Our research on AUTISM.
The development of better treatments for autism will be facilitated greatly by the identification of molecular targets that play a role in the pathophysiology of the disorder. Numerous studies demonstrate that autism is associated with cellular abnormalities in the anterior cingulate cortex. The anterior cingulate cortex mediates behaviors related to social interaction and disruption of social interaction is a core behavioral manifestation of autism. The specific cell types involved in anterior cingulate cortex dysfunction and the biochemical basis for this pathology in autism is unknown. My laboratory is keenly focused on identifying gene expression abnormalities independently in several cell types in the anterior cingulate cortex, including specific types of neurons and glia. For these studies, we use postmortem tissue from brain donors with previously diagnosed autism and matched typically developing brain donors. We use a variety of innovative methods to interrogate the molecular pathology of the anterior cingulate cortex, including combining laser capture microdissection of specific cell types with next generation sequencing to obtain whole cellular transcriptome analyses. Expression data is subjected to pathway analysis to evaluate potential involvement of signaling cascades in cellular pathology. Our research represents a novel exploration of neuronal and non-neuronal elements (i.e. astrocytes, oligodendrocytes) critical to neural transmission in autism. Elucidating molecular pathologies in these cell types in autism is anticipated to yield clues to the etiology of autism and has the potential to stimulate the development of diagnostic tools through identification of biomarkers. Most importantly, the proposed studies have the potential to identify unique molecular targets for therapeutic intervention, which could have a major impact on autism therapy given the paucity of pharmacological treatments for autism.
Szebeni A., Szebeni K., Chandley M.J., Stockmeier C.A., and Ordway G.A.: Shortened telomere length in white matter oligodendrocytes in major depression: potential role of oxidative stress. Int. J. Neuropsychopharmacology, 17:1579-1589, 2014. PMID: 24967945.
Fan Y., Chen P., Li Y. Ordway G.A., and Zhu M.-Y.: Effects of desipramine treatment on stress-induced upregulation of norepinephrine transporter expression in rat brain. Psychopharmacology, 232:379-390, 2015. PMID: 25038868
Crawford J.D., Chandley M.J., Szebeni K., Szebeni A., Waters B. and Ordway G.A.: Elevated GFAP protein in anterior cingulate cortical white matter in males with autism spectrum disorder. Autism Res. April 6, epub ahead of print; PMID: 25846779
Chandley M.J., Crawford J.D., Szebeni A., Szebeni K. and Ordway G.A.: NTRK2 expression levels are reduced in laser captured pyramidal neurons from the anterior cingulate cortex in males with autism spectrum disorder. Molecular Autism, 6:28-39, 2015. (ahead of Pubmed)
Ordway, G.A., Schwartz, M. and Frazer A.: Brain Norepinephrine: Neurobiology and Therapeutics, Cambridge University Press, 2007.