Functional Neuroanatomy of Cytokine-Mediated Anorexia

描述(由申请人提供)： 以下建议的基本目标是为应聘者提供新的正式接触小鼠遗传学和分子生物学方面的知识，以及功能神经解剖学/系统神经生物学方面的额外培训，所有这些都是在一个旨在深入研究具有重大基础和临床兴趣/意义的问题的研究计划的背景下进行的。食欲不振是治疗慢性病的障碍，包括某些癌症和病毒感染。从激活的免疫细胞释放的促炎细胞因子是调节这种厌食症的主要候选者，然而，对这种反应所涉及的神经通路和机制的完整了解仍然难以捉摸。以前的研究表明，某些神经化学系统(黑素皮质素和促肾上腺皮质激素释放因子(CRF))和作用部位(下丘脑室旁核和弓状核(PVH，ARH))参与了这一调节，但对潜在回路的组织和化学编码的清楚概述仍然难以捉摸。这项提议中的实验将跟踪基因表达与行为反应(食物摄入量减少)的变化，试图描述疾病引起的厌食症的功能神经解剖学框架。该建议的具体目标是(1)确定与疾病相关厌食相关的中枢结构，它们的肽能表型以及相关结构之间的通路的功能相关性(2)询问前阿片黑素皮质素(POMC)和黑素皮质素-4受体(MC4R)的具体参与，以及(3)研究CRF配体是否可能参与介导疾病引起的厌食，无论是下游的还是独立于MC4R激活的。拟议的研究将为候选人提供一个难得的机会，在索尔克研究所的功能神经解剖学(Paul Sawchenko博士)、遗传靶向(Kuo-Fen Lee博士)和病毒传递系统(Inder Verma博士)专家的指导下掌握各种新技术。这些研究建立在候选人先前研究的基础上，并为扩大研究问题的广度和深度提供了桥梁。在这些研究结束后，候选人将处于有利地位，可以获得一个独立的学术研究职位。

DESCRIPTION (provided by applicant): 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.