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Adipocyte metabolism and stem cell lineage responses

脂肪细胞代谢和干细胞谱系反应

基本信息

批准号：
10004144
负责人：
Daniela Drummond-Barbosa
金额：
$ 32.75万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-05 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004144
关键词：
Address Adenosine Adipocytes Affect Amino Acids Biological Process Body part Cell Count Cell Differentiation process Cell Lineage Cell Survival Coupled Data Daughter Diet Disease Drosophila genus Drug Prescriptions Drug Targeting Enzymes G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Goals Hematopoiesis Homologous Gene Hormones Human Immunity Insulin Link Macronutrients Nutrition Malignant Neoplasms Measures Metabolic Metabolic Diseases Metabolic Pathway Metabolism Nutrient Obesity Organ Organism Ovary Pathway interactions Phenotype Physiological Process Purinergic P1 Receptors Research Risk Role Signal Pathway Signal Transduction Sirolimus Testing Western World Work adult stem cell cancer cell extracellular germline stem cells in vivo insight knock-down receptor receptor-mediated signaling response self-renewal stem stem cell fate stem cell model stem cells steroid hormone tissue stem cells tool

项目摘要

Project Summary: Nutrients affect tissue stem cell lineages in all organisms. Interorgan signaling allows the impact of diet or physiological factors on one organ to be communicated to stem cell lineages elsewhere. Circulating levels of most energy substrates and metabolites vary with diet, and many of these activate G protein coupled receptors (GPCRs), which are associated with metabolic diseases, cancers and other disorders. It is therefore essential to investigate how GPCR signaling links metabolism to stem lineage processes in vivo. Adipocytes have key metabolic roles, and obesity increases the risk for many diseases. Among them are cancers, which share similarities with stem cells. Signaling pathways that control normal stem cells are often deregulated in cancers (e.g. diet-dependent pathways), and cancers and stem cells have large proliferative potential and generate differentiated cells in deregulated or controlled ways, respectively. The goal of this proposal is to study how diet controls adipocyte metabolism and how GPCR signaling mediates its effects on stem cell lineages using the Drosophila germline stem cell (GSC) model. Drosophila has highly conserved adipocyte metabolism and well characterized stem cells. One can readily identify GSCs and quantify self-renewal, proliferation, differentiation and survival along their lineage. GSCs and their progeny divide and grow faster on a rich diet, partially via insulin, steroid hormone, and Target of Rapamycin (TOR) signaling in the ovary. Adipocytes contribute to the GSC response to diet, as adipocyte-specific disruption of amino acid transport or TOR causes distinct GSC lineage phenotypes. Our unpublished data show that diet also regulates metabolic pathways in adipocytes, and key adipocyte enzymes influence GSC number, proliferation, and differentiation, survival of their daughters. In addition, our results show that distinct G proteins regulate GSC fate and division, and progeny survival, suggesting that GPCR signaling actively modulates the GSC lineage. We will test our hypothesis that key diet-dependent metabolic pathways in adipocytes control the levels of metabolites (or other downstream factors) that act directly on the ovary (or indirectly, through intermediate organs) to modulate the GSC lineage through the following aims: 1) To determine how macronutrients and diet-dependent hormones impact key adipocyte metabolic pathways; and 2) To probe the role of G protein coupled receptor (GPCR) signaling in the GSC lineage. Relevance: Obesity is prevalent in the western world and results in the abnormal function of fat cells, which in turn increases the risk for many diseases, including cancers. We propose to take advantage of powerful research tools in fruitflies to investigate how metabolic processes in fat cells normally generate signals that affect the function of stem cells in other parts of the body. Because of the high degree of evolutionary conservation of molecules and biological processes between fruitflies and humans, this work will likely provide valuable insights into diseases resulting from metabolic abnormalities in fat cells.

项目摘要：营养素影响所有生物体中的组织干细胞谱系。器官间信号传导允许饮食或一个器官上的生理因素被传递到其他地方的干细胞谱系。循环水平大多数能量底物和代谢物随饮食而变化，其中许多激活G蛋白偶联受体 GPCR是与代谢性疾病、癌症和其他疾病相关的基因。因此至关重要的研究GPCR信号如何将代谢与体内干细胞谱系过程联系起来。脂肪细胞是关键代谢的作用，肥胖增加了许多疾病的风险。其中包括癌症，与干细胞相似。控制正常干细胞的信号通路通常在癌症中失调 (e.g.饮食依赖途径），癌症和干细胞具有很大的增殖潜力，分别以去调节或受控的方式分化细胞。这项提案的目的是研究如何饮食控制脂肪细胞代谢以及GPCR信号传导如何介导其对干细胞谱系的影响果蝇生殖系干细胞（GSC）模型。果蝇具有高度保守的脂肪细胞代谢，干细胞的特征。人们可以容易地鉴定GSC并量化自我更新、增殖，分化和存活沿着它们的谱系。GSC及其后代在丰富的饮食中分裂和生长得更快，部分通过卵巢中的胰岛素、类固醇激素和雷帕霉素靶（TOR）信号传导。脂肪细胞有助于GSC对饮食的反应，因为脂肪细胞特异性破坏氨基酸转运或TOR会导致不同的GSC谱系表型。我们未发表的数据表明，饮食也调节代谢途径，脂肪细胞和关键脂肪细胞酶影响GSC的数量，增殖和分化，他们的女儿此外，我们的研究结果表明，不同的G蛋白调节GSC的命运和分裂，子代存活，表明GPCR信号积极调节GSC谱系。我们将测试我们的假设脂肪细胞中的关键饮食依赖性代谢途径控制代谢物（或其他代谢物）的水平，直接作用于卵巢（或通过中间器官间接作用于卵巢），以调节卵巢功能。 GSC谱系通过以下目的：1）确定大量营养素和饮食依赖性激素影响关键脂肪细胞代谢途径; 2）探讨G蛋白偶联受体（GPCR）的作用 GSC谱系中的信号传导。相关性：肥胖症在西方世界很普遍，脂肪细胞的功能，这反过来又增加了许多疾病的风险，包括癌症。我们建议采取在果蝇中使用强大的研究工具来研究脂肪细胞中的代谢过程如何正常产生影响身体其他部位干细胞功能的信号。由于高度的果蝇和人类之间的分子和生物过程的进化保守，这项工作将可能为研究脂肪细胞代谢异常引起的疾病提供有价值的见解。