PQ6 MECHANISMS OF CACHEXIA LIKE WASTING IN A DROSPHILA CANCER MODEL

果蝇癌症模型中恶病质样消瘦的 PQ6 机制

• 批准号: 8591196
• 负责人: David Bilder
• 金额: $ 12.35万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8591196
• 关键词: Adipose tissue; Adult; Benign; Biological Assay; Biology; Cachexia; Cancer Biology; Cancer Model; Cessation of life; Confusion; Data Set; Development; Drosophila genus; Face; Fatty acid glycerol esters; Functional disorder; Gene Expression; Gene Expression Profile; Genetic; Genetic Models; Goals; Growth; High-Risk Cancer; Homeostasis; Human; Immune response; Individual; Inflammation; Investigation; Lead; Learning; Malignant - descriptor; Malignant Neoplasms; Mammals; Mediating; Mediator of activation protein; Metabolic; Modeling; Molecular; Morbidity - disease rate; Muscle; Nature; Neoplasm Transplantation; Nutrient; Nutritional status; Organism; Pathway interactions; Patients; Peripheral; Physiology; Reporter; Research; Rodent; Signal Pathway; Signal Transduction; Signaling Molecule; Skeletal Muscle; Surveys; Syndrome; System; Testing; Therapeutic Intervention; Tissues; Transplantation; Wasting Syndrome; Xenograft procedure; base; effective therapy; fly; high risk; insight; meetings; mortality; mouse model; public health relevance; reproductive; research study; response; tumor; tumor growth; tumorigenesis; wasting

DESCRIPTION (provided by applicant): Cancer cachexia, a wasting syndrome characterized by the dramatic loss of skeletal muscle and adipose tissue, is perhaps the most poorly understood feature of cancer pathophysiology. Despite its major impact on patient morbidity and mortality, an understanding of the underlying mechanisms is quite primitive. While rodent tumor graft models have spurred existing insight, common principles of tumor signaling and host response remain obscure, and this void has limited development of effective therapies. In the face of such confusion, Drosophila can serve as a reductionist yet powerful alternative model. Malignant overgrowths that share features of human cancer can be readily created via Drosophila genetics, and the fly has a track record of contributions directly relevant to cancer biology. We have discovered that fly tumors introduced into wild-type hosts can induce a dramatic wasting-like response in peripheral host tissues, including loss of tissue mass with altered trophic signaling. The specific aim of this application is to identify the underlying mechanisms, with the goal of discovering common principles with human cancer cachexia and advancing insight into tumor-host tissue interactions in general. We will first capitalize on the rich understanding of Drosophila signaling biology (including functional necessity/sufficiency assays) to determine the pathways inducing wasting response in host tissues. We will next test both inflammation and altered nutrient signaling-based models for wasting. We will then uncover or rule out tumor-produced signals as instigators of host tissue wasting, leveraging unpublished transcriptome datasets from tumors that can and cannot induce wasting. Finally, we will investigate the applicability of the mechanisms uncovered in Drosophila to mammalian cachexia models. This proposal represents the first investigation of cachexia in a non-mammalian system, with all the experimental power that the flagship model genetic organism can bring. Despite the many differences between flies and humans and their cancers, this high-risk/high-gain project has strong potential to uncover fundamental and conserved pathways of tissue wasting, which could bring clarity to current confusion in the field and generate new directions for investigation.

描述（由申请人提供）：癌症恶病质是一种以骨骼肌和脂肪组织的巨大损失为特征的浪费综合征，也许是癌症病理生理学最了解的特征。尽管对患者的发病率和死亡率有重大影响，但对基本机制的理解仍然是原始的。尽管啮齿动物肿瘤移植模型刺激了现有的见解，但肿瘤信号传导和宿主反应的共同原理仍然晦涩难懂，并且该空隙的有效疗法的发展有限。面对这种混乱，果蝇可以作为还原主义但有力的替代模型。具有共享人类癌症特征的恶性过度生长可以通过果蝇遗传学很容易产生，而苍蝇具有与癌症生物学直接相关的贡献记录。我们发现，引入野生型宿主的蝇肿瘤可以在外围宿主组织中引起巨大的浪费样反应，包括随着营养信号的改变的组织质量损失。该应用的具体目的是确定潜在的机制，目的是发现具有人类癌症的常见原理，并促进对肿瘤宿主组织相互作用的洞察力。我们首先将利用对果蝇信号生物学的丰富理解（包括功能必要性/充分性测定），以确定宿主组织中诱导浪费反应的途径。接下来，我们将测试炎症和基于养分的基于营养信号的浪费模型。然后，我们将发现或排除肿瘤产生的信号作为宿主组织浪费的煽动者，从而利用可能也不能诱导浪费的肿瘤中未发表的转录组数据集。最后，我们将研究果蝇中发现的机制对哺乳动物的恶病质模型的适用性。该提案代表了非哺乳动物系统中的恶病质的首次研究，并具有旗舰模型遗传生物可以带来的所有实验能力。尽管苍蝇和人类及其癌症之间存在许多差异，但这个高风险/高增强项目具有探索组织浪费的基本和保守途径的强大潜力，这可能会使当前的混乱使现场混淆并产生新的调查方向。