(PQD6) Muscle stem cells and cancer cachexia

(PQD6) 肌肉干细胞和癌症恶病质

基本信息

批准号：
8719959
负责人：
Denis C Guttridge
金额：
$ 35.79万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-12 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8719959
关键词：
Acquired Immunodeficiency Syndrome Address Affect Amaze Area Atrophic Automobile Driving Basic Science Body Weight decreased Cachexia Cancer Etiology Cancer Patient Cells Cessation of life Chronic Disease Chronic Obstructive Airway Disease Clinic Diabetes Mellitus Diagnosis Employee Strikes Environment Equilibrium Event Fatigue Fiber Goals Heart failure Incidence Inflammation Inflammatory Bowel Diseases Injury Kidney Failure Knowledge Longevity Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of pancreas Morbidity - disease rate Muscle Muscle satellite cell Muscular Atrophy National Cancer Institute Operative Surgical Procedures Outcome Pancreas Pathology Pathway interactions Patients Perception Protein Biosynthesis Proteolysis Quality of life Radiation therapy Research Risk Role Sampling Severities Signal Pathway Signal Transduction Skeletal Muscle Solid Neoplasm Stem cells Survival Rate Syndrome Testing Translating Tumor Burden Weight Writing adverse outcome base cancer care chemotherapy cytokine effective therapy end stage disease experience human FRAP1 protein improved injured insight mortality mouse model muscle form outcome forecast progenitor programs public health relevance repaired response to injury satellite cell self-renewal stem cell population therapeutic target tool treatment response tumor tumor progression ubiquitin-protein ligase wasting

项目摘要

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.

描述（由申请人提供）：恶病质是一种衰弱的癌症综合征，导致由于骨骼肌的消耗而导致重量减轻。恶病质患者的预后差和贬值的生活质量。该综合征在大多数癌症中都普遍存在，但尤其与胰腺癌有关，估计表明85％的患者体重减轻。管理恶病质可能会取决于我们的能力，可以更好地了解驱动肿瘤引起的肌肉浪费的潜在机制，并且有了这些知识，越来越多的治疗靶标可以被识别并转化为诊所。这个概念是我们提议的基础，与NCI的挑衅性研究一致关于癌症恶病质的问题，以阐明启动患者恶病质的机制，并找到针对这些机制以延长寿命和生活质量的方法。我们最近的努力集中在肌纤维外和肌肉环境中发生的事件。我们发现肿瘤会引起损伤反应，从而引发肌肉干细胞激活和分化以修复受损的纤维，但是由于自我更新因子PAX7的放松管制，这种分化程序被阻止。该应用的目的是探讨以下假设：在肌纤维之外发生的事件不仅仅是发生癌症的后果，而是导致卡氏病理病理学的因果因素。为了实现这一目标，我们试图执行以下两个特定目标：1）表征造成肌肉浪费的肌源性干细胞； 2）阐明PAX7放松管制在癌症恶病质中的作用和机制。实现这一目标不仅可以洞悉癌症中肌肉浪费的机制和治疗靶标，而且还将扩大卡赫西亚研究的领域，到目前为止，该领域尚未被逐渐消失。