(PQD6) Muscle stem cells and cancer cachexia

描述(申请人提供)：恶病质是一种癌症衰弱综合征，由于骨骼肌耗尽而导致严重的体重减轻。恶病质患者预后差，生活质量下降。这种综合征在大多数癌症中普遍存在，但与胰腺癌尤其相关，据估计，85%的患者体重显著减轻。治疗恶病质很可能取决于我们是否有能力更好地了解导致肿瘤导致肌肉萎缩的潜在机制，有了这些知识，越来越多的治疗靶点可以被识别并转化到临床上。这一概念是我们建议的基础，与NCI的挑衅性研究是一致的 关于癌症恶病质的问题，以阐明在患者中引发恶病质的机制，并找到针对这些机制的方法，以延长寿命和生活质量。我们最近的努力集中在肌纤维外和肌肉环境内发生的事件上。我们发现，肿瘤会引发损伤反应，启动肌肉干细胞的激活和分化，以修复受损的纤维，但由于自我更新因子Pax7的解除调节，这种分化程序被阻止。该应用程序的目标是探索这样一种假设，即肌纤维外发生的事件不仅仅是癌症发展的结果，而是导致恶病质病理的原因因素。为了实现这一目标，我们试图实现以下两个具体目标：1)鉴定导致肌肉萎缩的肌源性干细胞；2)阐明Pax7去调控在癌症恶病质中的作用和机制。实现这一目标不仅将提供对癌症肌肉萎缩的机制和治疗目标的洞察，而且还将拓宽恶病质研究的一个领域，到目前为止，这一领域还没有得到充分的探索。

DESCRIPTION (provided by applicant): Cachexia is a debilitating syndrome of cancer that results in severe weight loss due to the depletion of skeletal muscle. Patients with cachexia have poor prognosis and a depreciating quality of life. This syndrome is prevalent in a majority of cancers, but is especially relevant for pancreatic cancer where estimates suggest that 85% of patients experience significant weight loss. Managing cachexia will likely hinge on our abilities t better understand the underlying mechanisms driving tumor-induced muscle wasting, and with this knowledge an increasing number of therapeutic targets can be identified and translated to the clinic. This notion is the basis of our proposal and is in line with NCI's provocative research question on cancer cachexia to elucidate mechanisms that initiate cachexia in patients and find ways to target these mechanisms to extend lifespan and quality of life. Our recent efforts have centered on events that occur outside the myofiber and within the muscle environment. We find that tumors elicit an injury response that initiates muscle stem cell activation and differentiatio to repair damaged fibers, but this differentiation program is blocked due to deregulation of the self-renewing factor, Pax7. The goal of this application is to explore the hypothesis that events occurring outside the myofiber are not simply consequences of a developing cancer, but instead causal factors that contribute to the pathology of cachexia. Towards this goal we seek to perform the following two specific aims: 1) Characterize the myogenic stem cells that contribute to muscle wasting; and 2) Elucidate the role and mechanism of Pax7 deregulation in cancer cachexia. Achieving this goal will not only provide insight into the mechanisms and therapeutic targets of muscle wasting in cancer, but will also broaden an area of cachexia research that, to this point, has been underexplored.