(PQD6) Hypothalamic Inflammation in the Initiation of Cachexia

描述(由申请人提供)：恶病质，或与疾病相关的消瘦，是癌症、肾功能衰竭和传染病的常见症状。这种毁灭性的营养不良状态是食欲下降和脂肪代谢和瘦体重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生活质量和最终死亡率的主要决定因素。其他由疾病引起的疾病，包括嗜睡，也损害了患者从潜在的挽救生命或延长干预措施中恢复的能力，并削弱了积极与这种疾病作斗争的动力。虽然慢性疾病中的恶病质早在两千多年前就被描述了，但这种能量平衡失调的核心机制却鲜为人知。此外，目前还没有有效的药物治疗。在过去的十年里，我们的实验室致力于解开恶病质的基础神经科学。在这项提案中，我们将重点了解下丘脑接受、放大和维持外周炎性损害的范围和机制。这项建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，以及针对了解近端神经炎性事件的新合作和努力。我们研究的长期目标是从机制上了解急性疾病的反应以及它是如何转变为慢性炎症相关的恶病质的，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.