(PQD6) Mechanistic insights into treatment of cancer anorexia and cachexia

(PQD6) 癌症厌食症和恶病质治疗的机制见解

• 批准号: 8684391
• 负责人: Michael W Schwartz
• 金额: $ 22.71万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8684391
• 关键词: Adult; Animals; Anorexia; Area; Bilateral; Body Weight; Body Weight decreased; Cachexia; Calcitonin; Calcitonin Gene-Related Peptide; Caloric Restriction; Cancer Etiology; Cancer Model; Cell Line; Cessation of life; Clinical; Desire for food; Diagnosis; Diet; Disease; Eating; Energy Metabolism; FOS gene; Fatty acid glycerol esters; Genetic; Homeostasis; Hypothalamic structure; Implant; Infection; Inflammation; Injection of therapeutic agent; Intake; Intervention; Laboratories; Letters; Lewis Lung Carcinoma; Malignant Neoplasms; Mediating; Modeling; Morbidity - disease rate; Mus; Muscle; Neurons; Outcome; Outcome Measure; Pain; Patients; Peptide Signal Sequences; Peptides; Pharmaceutical Preparations; Population; Prevention; Public Health; Quality of life; Radiation Leukemia Virus; Rattus; Role; Signal Transduction; Stimulus; Structure of nucleus infundibularis hypothalami; Synapsins; Technology; Testing; Thymoma; Transgenes; Weight Gain; Work; cancer anorexia; cancer therapy; clinical care; feeding; hindbrain; implantation; improved; increased appetite; innovation; insight; mortality; mouse model; muscle form; neuron loss; neuropeptide Y; novel; parabrachial nucleus; pre-clinical; prevent; promoter; public health relevance; response; skeletal muscle wasting; treatment strategy; tumor; tumor growth; virus genetics; wasting

DESCRIPTION (provided by applicant): Cancer cachexia/anorexia is a common, devastating manifestation of many malignancies and contributes significantly to patient morbidity and mortality. The etiology of cancer cachexia/anorexia is multifactorial and existing treatment strategies are disappointing. Recent work has identified calcitonin/calcitonin-gene relate peptide (CT/CGRP) neurons as the specific neuronal group in the hindbrain that causes anorexia and weight loss due to infection, inflammation and pain - and this same area of the hindbrain, the parabrachial nucleus, is known to be activated in pre-clinical cancer models. The novel genetic mouse models that elucidated the role of CT/CGRP neurons in 'illness' models of weight loss can also be used to definitively test the mechanistic role of these neurons in cancer cachexia/anorexia. Importantly, our proposed studies evaluate mouse cancer models causing gradual, progressive cachexia/anorexia - more similar to clinical situations. The novel genetic mouse models of inducible inhibition of CT/CGRP neurons allow us to investigate treatment strategies for cancer-induced weight loss rather than focusing merely on cachexia prevention. A second genetic strategy will focus on a key Arcuate nucleus neuronal population - NPY/Agrp neurons - and determine whether tumor- related inhibition of these neurons contributes to the mechanism of cancer cachexia/anorexia and whether inducible activation of these neurons can either prevent or treat established cancer cachexia/anorexia. Critically, our studies will also determine the impact of interventions to treat cancer anorexia on lean body mass and survival. Our proposal has the potential to discover novel therapies for treatment of cancer anorexia and thereby potentially improve the quality of life of patients with cancer.

描述（由申请人提供）：癌症恶病质/厌食症是许多恶性肿瘤的常见、破坏性表现，并且对患者的发病率和死亡率有显着影响。癌症恶病质/厌食症的病因是多因素的，现有的治疗策略令人失望。最近的工作已确定降钙素/降钙素基因相关肽（CT/CGRP）神经元是后脑中因感染、炎症和疼痛而导致厌食和体重减轻的特定神经元群 - 以及后脑的同一区域臂旁核，已知在临床前癌症模型中被激活。阐明 CT/CGRP 神经元在减肥“疾病”模型中作用的新型遗传小鼠模型也可用于明确测试这些神经元在癌症恶病质/厌食症中的机制作用。重要的是，我们提出的研究评估了导致逐渐、进行性恶病质/厌食症的小鼠癌症模型——更类似于临床情况。 CT/CGRP 神经元诱导抑制的新型基因小鼠模型使我们能够研究癌症引起的体重减轻的治疗策略，而不是仅仅关注恶病质的预防。第二个遗传策略将重点关注关键的弓形核神经元群 - NPY/Agrp 神经元 - 并确定这些神经元的肿瘤相关抑制是否有助于癌症恶病质/厌食症的机制，以及这些神经元的诱导激活是否可以预防或治疗确诊癌症恶病质/厌食症。至关重要的是，我们的研究还将确定治疗癌症厌食症的干预措施对去脂体重和生存的影响。我们的建议有可能发现治疗癌症厌食症的新疗法，从而有可能改善癌症患者的生活质量。