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The overall objective of the Translational Neuroscience Program, directed by David A. Lewis, MD, is to understand the neurobiological basis for complex human cognitive and emotional functions, and the manner in which alterations in the brain give rise to the types of disturbances in these functions that characterize psychiatric disorders. Disorders of particular interest include schizophrenia, bipolar disorder, major depressive disorder, addiction, and Alzheimer disease with psychosis. In pursuit of this goal, Program scientists seek to "translate" clinical observations into hypotheses about the biological mechanisms involved in a disease process that can be tested in the more tractable conditions of the laboratory in order to guide the identification of molecular targets for drug development. Indeed, the principal motivation for these studies is the acquisition of the knowledge needed to develop novel approaches for improving the treatment and prevention of these disorders.

The research strategies utilized by the Translational Neuroscience Program are designed to dissect the disease process of interest. As illustrated in the schematic diagram below, Program investigators seek to explore how certain etiological factors, or causes of an illness, can unleash pathogenic mechanisms that produce pathological disturbances in the brain, and how these brain disturbances give rise to the pathophysiological processes that alter brain function and are manifest as a particular clinical syndrome. Understanding pathophysiology is critical to the rational development of new treatments that can reverse these processes, resulting in the amelioration of the signs and symptoms of an illness. Similarly, understanding pathogenesis is essential for the development of secondary forms of disease prevention.

Because brain pathology occupies the center point of this series of events, Program research activities focus on identifying the nature of the brain disturbances in major psychiatric illnesses. Any observed brain pathology may represent any of the following four "Cs": 1) an upstream cause related to the disease process, 2) a deleterious consequence of a cause, 3) a compensation, resulting from either a cause or consequence, that attempts to restore homeostasis, or 4) a confound that is associated with the disease but not a part of the disease process. By identifying the nature or type of each observed alteration, Program scientists are able to dissect and develop models of the disease process that guide investigations into disease pathogenesis and pathophysiology, enabling the identification of novel targets and the development of interventions directed against those targets.

Schematic summary of the components of the disease process of schizophrenia. According to this view, the etiology (or cause) of the illness unleashes pathogenic processes that lead to discrete pathological entities, each of which alter normal brain circuitry and function. The resulting pathophysiology gives rise to the distinct components of the clinical syndrome of schizophrenia. The development of effective treatments or preventative measures requires the ability to interrupt or reverse the pathophysiological processes and pathogenic mechanisms, respectively. From Lewis DA, Sweet RA: Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies. Journal of Clinical Investigation 119:706-716, 2009.

David A. Lewis, MD | Department of Psychiatry | University of Pittsburgh
3811 O'Hara Street | Biomedical Science Tower W1654 | Pittsburgh, Pennyslvania 15213-2593 - Phone: (412) 383-8548 - Fax: (412) 624-9910