(PQD6) Hypothalamic Inflammation in the Initiation of Cachexia

描述（由申请人提供）：恶病质，或疾病相关消耗，在癌症、肾衰竭和传染病中常见。这种毁灭性的营养不良状态是由食欲下降和脂肪和瘦肉代谢增加的协同作用造成的。在许多疾病中，恶病质的严重程度是决定生活质量和最终死亡率的主要因素。包括嗜睡在内的其他疾病引起的发病率也损害了患者从可能挽救生命或延长干预措施中恢复的能力，并削弱了积极对抗这种疾病的动力。尽管早在两千多年前就有关于慢性疾病中的恶病质的描述，但人们对这种能量稳态紊乱的主要机制知之甚少。此外，目前还没有有效的药物治疗。在过去的十年里，我们的实验室一直致力于揭开恶病质的基本神经科学原理。在本建议中，我们将重点了解下丘脑接收、放大和维持外周炎症损伤的范围和机制。这项提议的意义在于它独特地结合了我们对神经内分泌学和行为的历史关注，以及针对近端神经炎症事件的新合作和努力。我们研究的长期目标是获得急性疾病反应的机制理解，以及它如何转变为慢性炎症相关的恶病质，以便开发更有效的治疗干预措施。

DESCRIPTION (provided by applicant): Cachexia, or disease-associated wasting, is a common occurrence in cancer, renal failure, and infectious disease. This devastating state of malnutrition is brought about by a synergistic combination of a decrease in appetite and an increase in metabolism of fat and lean body mass. The severity of cachexia in many illnesses is the primary determining factor in both quality of life, and in eventual mortality. Other illness-induced morbidities including lethargy also compromise the ability of patients to recover from potentially life-saving or extending interventions, and diminish the motivational drive to aggressively battle the condition. Although cachexia in chronic disease was described more than two thousand years ago, the central mechanisms underlying this disorder of energy homeostasis are poorly understood. Furthermore, there is currently no effective pharmaceutical treatment. Our laboratory has dedicated the last decade to unraveling the basic neuroscience of cachexia. In this proposal, we will focus on understanding the scope and mechanism by which peripheral inflammatory insults are received, amplified, and maintained by the hypothalamus. The significance of this proposal resides in its unique combination of our historical focus on neuroendocrinology and behavior, with new collaborations and efforts directed at understanding proximal neuroinflammatory events. The long-term goal of our research is to gain mechanistic understanding of the acute illness response and how it is transitioned into chronic inflammation-associated cachexia in order to develop more effective therapeutic interventions.