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候选人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，所有这些都是在旨在渗透实质性基础和临床兴趣/意义问题的研究计划背景下进行的。食欲不振是治疗慢性疾病的一个障碍，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介导这种厌食症的主要候选者，但对参与这种反应的神经通路和机制的完整理解仍然是难以捉摸的。以前的工作涉及某些神经化学系统（黑皮质素和促肾上腺皮质激素释放因子（CRF））和作用部位（室旁核和下丘脑弓状核（PVH，ARH））参与调解，但组织和化学编码的基本电路的清晰的概述仍然难以捉摸。在这个提议中的实验将跟踪基因表达的变化与行为反应（减少食物摄入量）平行，试图描述疾病引起的厌食症的功能神经解剖学框架。该提案的具体目标是（1）鉴定与疾病相关的厌食症相关的中心结构、其肽能表型以及相关结构之间途径的功能相关性（2）询问阿黑皮素原（POMC）和黑素皮质素的具体参与4受体（MC 4 R）和（3）调查CRF配体是否可能参与介导疾病诱导的厌食症，下游或独立于MC 4 R激活。拟议的研究将为候选人提供一个特殊的机会，在功能神经解剖学（Paul Sawchenko博士），遗传靶向（Kuo-Fen Lee博士）和病毒递送系统（Inder Verma博士）专家的指导下掌握各种新技术，所有这些都在索尔克研究所进行。这些研究建立在候选人先前的研究基础上，并提供了一个桥梁，以扩大所解决的研究问题的广度和深度。在这些研究的结论，候选人将很好地定位，以获得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.