CYTOKINES IN THE PATHOPHYSIOLOGY OF ANOREXIA IN AGING

衰老厌食症病理生理学中的细胞因子

基本信息

批准号：
6178015
负责人：
Rodney W Johnson
金额：
$ 11.93万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-08-01 至 2002-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (Adapted from the Applicant's Abstract): Progressive anorexia and cachexia are common in elderly individuals and are major factors contributing to premature death and disability. The cytokine IL-1B is acknowledged to be involved in normal aging, but its role in this complex has been largely ignored because in the absence of infectious or autoimmune disease, plasma IL-1B does not correlate with anorexia and cachexia of aging. Most research concerning IL-1B has centered on its peripheral effects, but the investigator contends that any search for the true cause of anorexia and cachexia of aging should include the role of IL-1B in the brain. New data obtained in the investigator's laboratory show that IL-1B is 100- to 500-fold more effective for inducing weight loss and depressing motivation for food when administered into a lateral ventricle of the brain (icv) compared to in the periphery. Moreover, he has now shown that aged rodents lose substantially more body weight than mature adults following icv injection of recombinant IL-1B. The broad working hypothesis is that the anorexia and cachexia of aging are caused directly by IL-1B within the CNS. The proposed experiments will be conducted in mice because of the availability of recombinant murine cytokines, specific receptor antagonists, and ICE knockouts. They will assess the motivation of mice to eat as an in vivo readout for icv administration of recombinant murine IL-1B, as well as other features of cachexia including plasma urea nitrogen, serum triglycerides, weight loss and body composition. In their first objective, they will compare the anorectic and cachectic properties of IL-1B-injected icv in mature adult and aged mice. The PI will test the most critically important possibilities for CNS-controlled anorexia and cachexia, including effects of constant icv infusion of IL-1B and potential synergism between IL-1B and TNFa. For the hypothesis to be correct, salient features of the brain cytokine network must differ between aged and adult mice. Therefore, in the second objective he will employ cellular and molecular strategies to characterize ICE, IL-1B, and type I and type II IL-1 receptors in the brain of aged mice. Finally, in objective 3 the PI will explore alternative approaches for alleviating anorexia and cachexia caused by IL-1B in the CNS. Specifically, he will determine which IL-1 receptor isoform is responsible for inducing anorexia and cachexia in vivo and will test the new idea that ICE knockouts are refractory to the metabolic effects of inflammatory stimuli in the brain.

描述（改编自申请人的摘要）：渐进厌食症恶病质在老年人中很常见，是主要因素导致过早死亡和残疾。细胞因子IL-1B是被公认参与正常衰老，但其在这个复合物中的作用由于没有传染性或自身免疫性，因此在很大程度上被忽略了疾病，等离子体IL-1B与厌食和恶病质无关老化。关于IL-1B的大多数研究都集中在其周围效果，但调查人员认为，任何寻找真正原因厌食症和衰老的缓存应包括IL-1B的作用脑。在研究者的实验室中获得的新数据表明IL-1B 100至500倍以诱发体重减轻和下降效率更高当施用到大脑的侧心室中时，食物的动机（ICV）与外围相比。而且，他现在已经表明了 ICV之后，啮齿动物的体重比成熟的成年人高得多注入重组IL-1B。广泛的工作假设是衰老的厌食症和恶病症是直接由CNS内的IL-1B引起。提出的实验将是由于重组鼠的可用性，在小鼠中进行细胞因子，特定的受体拮抗剂和冰敲门。他们会的评估小鼠吃作为ICV的体内读数的动机重组鼠IL-1B以及其他特征缓存包括血浆尿素氮，血清甘油三酸酯，减肥和身体成分。在他们的第一个目标中，他们将比较 IL-1B的成年成年和厌恶性ICV的厌食和缓存特性老鼠。 PI将测试最重要的可能性中枢神经系统控制的厌食和恶病质，包括恒定ICV的影响 IL-1B的输注以及IL-1B和TNFA之间的潜在协同作用。为了假设是正确的，脑细胞因子网络的显着特征老年小鼠和成年小鼠必须有所不同。因此，在第二个目标中他将采用细胞和分子策略来表征ICE，IL-1B，以及年龄小鼠大脑中的I型和II型IL-1受体。最后，在目标3中，PI将探索缓解的替代方法中枢神经系统中IL-1B引起的厌食症和恶病质。具体来说，他会的确定哪种IL-1受体同工型负责诱导厌食和病原体在体内，并将测试冰敲除的新想法对大脑炎症刺激的代谢作用的难治性。