(PQD6) Muscle stem cells and cancer cachexia

描述（由申请人提供）：恶病质是一种使人衰弱的癌症综合症，由于骨骼肌的消耗导致体重严重下降。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。管理恶病质可能取决于我们是否有能力更好地理解驱动肿瘤诱导的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确定并转化为临床。这个概念是我们提议的基础，并且与NCI的挑衅性研究一致

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.