Exosomes as Endocrine Signaling Molecules in Cancer Cachexia

项目摘要： 疾病行为和代谢紊乱在胰腺癌患者中很常见，并可能导致 消瘦或恶病质。这种毁灭性的营养不良状态是由以下因素的协同作用造成的： 食欲下降，脂肪和瘦体重代谢增加。恶病质的严重程度 许多疾病是生活质量和最终死亡率的主要决定因素。其他疾病- 诱发的疾病，包括嗜睡，也损害了病人从挽救生命或 延长干预措施，并减少积极与病情作斗争的动力。虽然 癌症患者的恶病质早在两千多年前就有描述， 对这种疾病的潜在原因知之甚少。此外，目前还没有有效的药物 治疗我们的实验室致力于揭开恶病质的基础神经科学。在本提案中，我们 将侧重于了解胰腺癌发展信号的范围和机制， 由下丘脑接收、放大和维持。这项建议的意义在于， 我们对神经内分泌学和行为的历史重点的独特组合，与新的合作， 致力于理解细胞外囊泡在神经炎症中的作用。的长期目标 我们的研究是为了获得对急性疾病反应的机制性理解，以及它是如何转变为 慢性炎症相关的恶病质，以便开发更有效的治疗干预。

Project Summary: Illness behaviors and metabolic disturbances are common in pancreatic cancer patients, and may lead to wasting or cachexia. 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 life-saving or extending interventions, and diminish the motivational drive to aggressively battle the condition. Although cachexia in cancer patients was described more than two thousand years ago, the central mechanisms underlying this disorder are poorly understood. Furthermore, there is currently no effective pharmaceutical treatment. Our laboratory is dedicated to unraveling the basic neuroscience of cachexia. In this proposal, we will focus on understanding the scope and mechanism by which signals of pancreatic cancer development 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 the role of extracellular vesicles in neuroinflammation. 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.