EXCEED THE SPACE PROVIDED. This application is to support the career development of Dr. Gregory A. Ordway as an independent scientist in mental he'.alth research. The candidate has a 15 year history in mental health research and has been funded by NIMH during th s time. His primary area of research has focused on the role of the central noradrenergic system in the pathology of degression, as well as on molecular mechanisms of noradrenergic antidepressant drugs. The PI proposes to continue his research to elucidate the basic neurochemical pathology of depression with the intention of revealing novel targets fo pharmacological or genetic intervention. The proposed career development includes educational activities to enhance and broaden the Pi's knowledge base, mini-sabbaticals to advance and improve the Pi's technical skills, and activities to strengthen collaborations. Together, the proposed career enhancement activities are designed to facilitate ard enhance the research career of the PI. The proposed research will, in part, test the hypothesis that a distinct constellation of neurochemical/neuroanatomical deficits occurs in the noradrenergic system (in particular, the locus coeruleus; LC) in major depression. Concentrations of specific proteins will be measured throughout the LC, and in a major limbic projection area (amygdala) in post-mortem brains from subjects with major depression at the time of death, subjects with other psychiatric illnesses (to address specificity), and from psychiatrically normal control subjects. Preliminary data reveals low levels of norepinephrine transporter (NET) in the LC of antidepressant-free major depressive subjects relative to control subjects. These and other data imply that depression is associated with a norepinephrine deficiency, and further suggest that NET regulation in humans is relevant to noradrenergic homeostasis and depression biology. Recently, the P.I. showed that the NET is robustly downregulated in response to exposureto certain NET inhibitors. The regulation of NET function induced by NET ligands is poorly understood but may contribute to their mechanism of therapeutic action. A second component of the proposed research is to elucidate the molecular mechanisms responsible for ligand-induced regulation of the NET. The ability of NET ligands to induce NET regulation in in vitro (cell culture) and in vivo (rat) preparations will be studied, and the molecular mechanisms responsible for those effects will be investigated. Emphasis will be placed on temporal aspects of NET regulation and recovery, because slow recovery from inhibitor-induced down-regulation may imply that reduced uptake exceeds antidepressant presence in vivo. This information could significantly impact treatment regimens of NET inhibitors for management of depression. Overall, the proposed studies will reveal pathology of noradrenergic neurons in depression, clues relevant to new pharmacotherapeutic or genetic targets, and molecular mechanisms of NET ligand antidepressants. PERFORMANCE SITE ========================================Section End===========================================
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