(PQD6) Hypothalamic Inflammation in the Initiation of Cachexia

描述（由申请人提供）：恶病质或疾病相关性消瘦在癌症、肾衰竭和感染性疾病中常见。这种破坏性的营养不良状态是由食欲下降和脂肪和瘦体重代谢增加的协同组合带来的。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。包括嗜睡在内的其他疾病引起的发病率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，并削弱了积极对抗病情的动力。虽然早在两千多年前就有人描述过慢性疾病中的恶病质，但对这种能量稳态紊乱的中枢机制却知之甚少。此外，目前还没有有效的药物治疗。我们的实验室在过去的十年里致力于揭示恶病质的基础神经科学。在这个建议中，我们将集中在了解的范围和机制，外周炎症损伤的接收，放大，并保持下丘脑。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，以及针对理解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对急性疾病反应的机制性理解，以及它如何转变为慢性炎症相关的恶病质，以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.