The purpose of the current K23 application is to provide support for the candidate's development into a highly productive independent clinical investigator in the pathogenesis of depression. A comprehensive five-year career development and research plan will be undertaken with the mentorship of Dr. Lawrence H. Price, an established senior scientist with internationally recognized expertise in neurobiological investigations of depression and extensive experience mentoring junior faculty. In addition, a team of comentors and consultants has been assembled to provide expert guidance in the training and research components of the proposed award. The Career Development Plan has been carefully designed to provide in-depth training in the following domains: the neurobiology of depression and the hypothalamic-pituitary-adrenal (HPA) axis, the role of stress and adversity in the pathogenesis of depression, the neuropsychology of depression and neuroendocrine function, and research ethics and methodology. In addition, further training in longitudinal methodology will be undertaken in preparation for a prospective, longitudinal R01 submission in Year 4-5 of the award. Formal training in these areas will be obtained through a curriculum of intramural and extramural didactics and coursework, preceptorships, research, research group meetings, and participation in national research meetings. The proposed research plan involves an examination of stress hormone responses to neuroendocrine challenge tests in relation to family history of depression and history of childhood adversity. Secondly, associations between HPA dysregulation and cognitive functioning will be investigated. This study offers the potential for substantial insight into the pathogenesis of depression and the effects of early-life stress and hyperactivity of the HPA axis. Results of this study, in combination with training in the design, implementation, and analysis of longitudinal studies, will comprise the basis of an R01 to be submitted at the beginning of Year 5. This R01 proposal will entail a prospective longitudinal investigation of the effects of childhood adversity and maternal mood and anxiety disorders on the development of neuroendocrine dysfunction and psychopathology.
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