The candidate's research record demonstrates a commitment to a career in biomedical research and, specifically, to understand the regulation of catecholamine (CA) systems physiology and their role in neuropsychiatric disease. Randy Blakely, serving as mentor of this application, has an outstanding research record and has mentored numerous postdoctoral fellows to successful careers as independent investigators. With the guidance of a mentoring committee, whose members are Ariel Deutch, Danny Winder and David Robertson, all experts in catecholamine system physiology and disease processes, we have incorporated into this application the components we deem critical to the candidate's scientific development. The application will provide novel training in the area of transgene expression of norepinephrine transporter genetic variants in primary noradrenergic neuronal culture and genetically altered mice, including use of immunofluorescence microscopy, transport assays and behavioral analyses to understand the impact of norepinephrine transporter genetic variants. Under the career development plan the candidate will participate in courses and seminars to receive didactic training and has also arranged to serve as instructor in several Vanderbilt courses. Vanderbilt University offers a superior environment to conduct the activities under this award, including core facilities for transgenic mouse production, mouse behavioral analysis and confocal microscopy. This application proposes approaches not presently applied in the Blakely laboratory to the study of the norepinephrine transporter, thus providing some novel and independent avenues of research. The candidate's successful publication record, recognition by various awards and fellowships and continued drive to learn and teach others through conferences, classroom teaching, or in the laboratory, demonstrate an exuberance, commitment and potential for success as an independent scientist. ? Relevance: The norepinephrine (NE) transporter (NET), is a mediator of NE inactivation by reuptake of NE into cells and may play a role in disorders of cardiovascular function, attention, memory and mood. Variation in NET genetic sequence, leading to altered NET protein, has been identified in humans. Selected genetic variants will be expressed in cells for activity and in mice for cardiovascular function and behaviors linked to memory and attention. Understanding the function of NET variants will contribute to our understanding of how genetic variation within NET contributes to human complex traits and disease ? ?
|Shirey-Rice, Jana K; Klar, Rebecca; Fentress, Hugh M et al. (2013) Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome. Dis Model Mech 6:1001-11|
|Fentress, H M; Klar, R; Krueger, J J et al. (2013) Norepinephrine transporter heterozygous knockout mice exhibit altered transport and behavior. Genes Brain Behav 12:749-59|
|Hahn, Maureen K; Steele, Angela; Couch, R Steven et al. (2009) Novel and functional norepinephrine transporter protein variants identified in attention-deficit hyperactivity disorder. Neuropharmacology 57:694-701|
|Hahn, M K; Blackford, J U; Haman, K et al. (2008) Multivariate permutation analysis associates multiple polymorphisms with subphenotypes of major depression. Genes Brain Behav 7:487-95|
|Hahn, Maureen K; Blakely, Randy D (2007) The functional impact of SLC6 transporter genetic variation. Annu Rev Pharmacol Toxicol 47:401-41|