Brainstem Mechanisms of Cachexia

描述（由申请人提供）：恶病质或疾病相关消耗是许多慢性疾病治疗中的一个重要问题。先前的研究表明，黑素皮质素中枢系统在引入黑素皮质素拮抗剂减轻炎症的恶病质反应这一过程中起着重要作用。我们的实验室已经证明，下丘脑弓状核中产生促阿皮黑素- (POMC-)的神经元在炎症期间被激活，大约35%的弓状POMC神经元表达细胞因子受体。脑干也是POMC表达的部位，由于脑干参与产生恶病质中观察到的许多生理过程，我们一直在研究引入IL-1后脑干中表达POMC的神经元的反应。我们发现，IL-1暴露后，具有c-fos激活和电活动的POMC细胞数量显著增加。我们建议研究这种作用是通过直接激活还是间接激活产生的，以及其他细胞因子是否在脑干的POMC神经元中产生类似的激活。我们进一步建议通过药物手段研究脑干黑素皮质素活性被阻断时的生理反应。

DESCRIPTION (provided by applicant): Cachexia or disease-associated wasting is a significant problem in the treatment of many chronic diseases. Prior research has implicated the central melanocortin system as playing an important role in this process seen in that introduction of melanocortin antagonists attenuates cachexic responses to inflammation. Our lab has shown that pro-opiomelanocortin- (POMC-) producing neurons in the arcuate nucleus of the hypothalamus are activated during inflammation and that approximately 35% of arcuate POMC neurons express cytokine receptors. The brainstem is also a site of POMC expression and because the brainstem is involved in producing many of the physiologic processes observed in cachexia, we have been investigating the response of POMC-expressing neurons in the brainstem following introduction of IL-1. We have found a significant increase in the amount of POMC cells with c-fos activation and electrical activity following IL-1 exposure. We propose to study whether this effect is produced via direct or indirect activation and whether other cytokines produce a similar activation in POMC neurons in the brainstem. We further propose to study the physiologic response seen when brainstem melanocortin activity is blocked via pharmicologic means.