The Role of Hypoketonemia in the Cancer Anorexia-Cachexia Syndrome

项目摘要/摘要 这项提议描述了一项为期五年的培训计划，旨在在 内分泌学和癌症生物学的交集。这位候选人是威尔康奈尔大学的内分泌学研究员 医学中心，十多年来一直在培养成为一名内科科学家。建议数 研究将在刘易斯·C·坎特利博士的指导下进行，他是癌症生物学领域的领军人物 和生物化学，他培养了无数年轻的研究人员。由有才华的科学家组成的顾问委员会 还收集了一些关于职业发展和实验的指导。这项研究 环境提供了广泛的资源、核心设施和智力专长。因此，这是一种理想 培养成为独立内科医生-科学家所需技能的培训环境。参与 在教学课程和专业发展方面，研讨会将提高项目的教育成功。 癌症厌食-恶病质综合征(CACS)是一种全身性代谢紊乱，其特征是 营养丰富的组织的分解代谢，如肌肉和脂肪组织。患有CACs的患者减少了 行动不便，生活质量恶化，生存时间缩短。限制肌肉流失的治疗策略是 预计将逆转这些有害的结果，独立于直接的癌症治疗。CACS没有有效的 治疗或已知的病因，部分原因是动物模型不能很好地模拟患者的发现。但是，在 可诱导的非小细胞肺癌基因工程小鼠模型的初步实验 (NSCLC)，申请人已经确定并表征了一种可靠地在人类体内复制CAC的模型。这些 小鼠表现出独特的代谢特征，其特征是通过以下方式丧失依赖于PPARα的酮的产生 肝脏和内源性糖皮质激素水平的上升。使用PPARα激动剂恢复酮的生产， 非诺贝特，减少糖皮质激素，防止骨骼肌群和体重的减少。 这一建议在初步实验的基础上进行了扩展，试图澄清 非小细胞肺癌相关CACs全身代谢和骨骼肌丢失的观察变化。这个 提出的目标是检验骨骼肌退化是由酮的丧失引起的假设。 生产(目标1)或随后糖皮质激素的增加(目标2)。此外，这项提案将寻求 确定启动CACS小鼠肝脏PPARα表达降低的肿瘤释放因子(目的 3)。这些实验将阐明驱动肌肉丧失的系统代谢信号在动物模型中的作用 准确模拟观察到的临床症状的非小细胞肺癌。我们的期望是识别特定的肿瘤- 分泌的蛋白质减少肝酮的产生，并证明酮替代疗法是一种 有用的治疗策略。这些结果不仅将加深我们对CACS发起的理解，而且还将 突出未来治疗的新途径。

Project Summary/Abstract This proposal describes a five-year training program to launch a research career in a novel niche at the intersection between endocrinology and cancer biology. The candidate is an endocrinology fellow at Weill Cornell Medical Center, who has been training to become a physician-scientist for over ten years. The proposed research will be carried out under the mentorship of Lewis C. Cantley, PhD, a leader in the field of cancer biology and biochemistry who has trained numerous young investigators. An advisory committee of talented scientists has also been assembled to offer guidance in career development and experimentation. The research environment provides extensive resources, core facilities, and intellectual expertise. Therefore, it is an ideal training setting in which to develop the requisite skills to become an independent physician-scientist. Participation in didactic courses and professional development seminars will enhance the educational success of the program. The cancer anorexia-cachexia syndrome (CACS) is a systemic metabolic disorder characterized by the catabolism of nutrient-rich tissues, such as muscle and adipose tissue. Patients with CACS have reduced mobility, worsened quality of life, and shortened survival. Therapeutic strategies to limit muscle loss are predicted to reverse these deleterious outcomes, independent of direct cancer treatment. CACS has no effective treatment or known etiology, in part, because animal models poorly mimic the findings in patients. However, in preliminary experiments using an inducible, genetically engineered mouse model of non-small cell lung cancer (NSCLC), the applicant has identified and characterized a model that reliably replicates CACS in humans. These mice display a unique metabolic profile, characterized by the loss of PPARα-dependent ketone production by the liver and a rise in endogenous glucocorticoid levels. Restoring ketone production using the PPARα agonist, fenofibrate, reduces glucocorticoids and prevents the loss of skeletal muscle mass and body weight. This proposal expands upon the preliminary experiments and seeks to clarify the causal relationship between the observed changes in systemic metabolism and skeletal muscle loss in NSCLC-associated CACS. The proposed aims are to test the hypothesis that skeletal muscle degradation results from the loss of ketone production (Aim 1) or the subsequent rise in glucocorticoids (Aim 2). Additionally, this proposal will seek to identify the tumor-released factor that initiates the reduction in hepatic PPARα expression in CACS mice (Aim 3). These experiments will elucidate the systemic metabolic signals driving muscle loss in an animal model of NSCLC that accurately mimics the observed clinical syndrome. The expectations are to identify specific tumor- secreted proteins that reduce hepatic ketone production, and demonstrate that ketone replacement therapy is a useful therapeutic strategy. These results will not only further our understanding of CACS initiation, but will also highlight novel pathways on which to base future therapy.