The basic goal of the following proposal is to provide the candidate with new formal exposure to aspects of mouse genetics and molecular biology, and additional training in functional neuroanatomy/systems neurobiology, all in the context of a research program designed to penetrate a problem of substantial basic and clinical interest/significance. Loss of appetite is an obstacle in the treatment of chronic illness, including certain cancers and viral infections. Proinflammatory cytokines released from activated immune cells are prime candidates for mediating this anorexia, yet a complete understanding of the neural pathways and mechanisms involved in this response remains elusive. Previous work has implicated certain neurochemical systems (melanocortins and corticotropin-releasing factor (CRF)) and sites of action (paraventricular and arcuate nuclei of the hypothalamus (PVH, ARH)) as involved in the mediation, but a clear overview of the organization and chemical coding of the underlying circuitry has remained elusive. Experiments in this proposal will track changes in gene expression in parallel with behavioral responses (decreased food intake) in an attempt to describe the functional neuroanatomical framework of sickness-induced anorexia. The specific goals of this proposal are to (1) identify central structures involved in illness-associated anorexia, their peptidergic phenotype and the functional relevance of pathways between involved structures (2) interrogate the specific involvement of proopiomelanocortin (POMC) and melanocortin-4 receptor (MC4R) and (3) investigate whether CRF ligands may be involved in mediating sickness-induced anorexia, either downstream or independently of MC4R activation. The proposed studies will provide the candidate an exceptional opportunity to master a variety of new techniques under the guidance of experts in functional neuroanatomy (Dr. Paul Sawchenko), genetic targeting (Dr. Kuo-Fen Lee), and viral delivery systems (Dr. Inder Verma), all at the Salk Institute. These studies build on the candidate's prior research, and provide a bridge to expand the breadth and depth of research questions addressed. At the conclusion of these studies, the candidate will be well positioned to obtain an independent academic research position.
