Ecdysone signaling and the dietary control of oogenesis in Drosophila

果蝇蜕皮激素信号传导和卵子发生的饮食控制

• 批准号: 7904427
• 负责人: Elizabeth Tweedie Ables
• 金额: $ 0.31万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-31 至 2010-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904427
• 关键词: Drosophila genus; Ecdysone; Oogenesis; Signal Transduction; dietary control

DESCRIPTION (provided by applicant): Several lines of evidence suggest that the growth of many cancers is maintained by a small population of cancer stem cells. Cancer stem cells share properties of embryonic and adult stem cells. Indeed, cell transformation and cancer growth are controlled by the same cell-cell communication pathways used by stem cells to promote self-renewal and pluripotency. High calorie diets and increased insulin and steroid hormone levels are known to increase cancer risk. This correlation is especially important in light of the increasing obesity epidemic in the U.S. and abroad. However, the connection between these factors and tumor growth or cancer stem cell proliferation has not been clearly defined. Thus, understanding the molecular mechanisms by which normal stem cells respond to nutritionally regulated signals will yield new insights into the regulation of cancer growth. To explore these mechanisms, we use the Drosophila ovary as a model system to study the control of stem cell activity by diet. Our laboratory has demonstrated that the ovary rapidly responds to changes in diet by altering stem cell division rates, germline cell growth, and follicle cell proliferation. This process requires the direct stimulation of the germline by neural-derived insulin signals. Recent evidence from other laboratories has suggested that the effects of insulin on larval growth are counteracted by ecdysone, a steroid hormone structurally and evolutionarily related to human estrogen. Ecdysone has known roles in oogenesis, including coordination of border cell migration and follicle cell differentiation. Additionally, loss of ecdysone signaling prevents progression of egg chambers through vitellogenesis; however, it is unknown whether ecdysone signaling connects the rate of oogenesis and diet, or whether ecdysone modulates insulin signaling in the ovary. The goal of this proposal is to understand the mechanisms by which ecdysone and insulin signaling may act together to control ovarian stem cells in response to changes in diet. To test the hypothesis that ecdysone signaling modulates the insulin pathway to control the ovarian response to diet, we will use loss-of-function mutations in the ecdysone pathway to determine if ecdysone signaling is involved in the response to diet. We will also determine which cell types in the ovary receive and respond to the ecdysone signal. Lastly, we will investigate whether ecdysone signaling may antagonize or cooperate with the stimulatory effects of insulin on rates of stem cell proliferation, and probe the relevant mechanisms involved. Understanding the molecular mechanisms by which normal adult stem cells respond to diet, steroid hormones, and insulin will be highly beneficial for the development of new therapies for cancer targeted at the level of the supporting stem cells.

描述（由申请人提供）：几条证据表明，许多癌症的生长是由少量癌症干细胞维持的。癌症干细胞具有胚胎和成年干细胞的特性。实际上，细胞转化和癌症生长受到干细胞用来促进自我更新和多能性的相同细胞 - 细胞通信途径的控制。高热量饮食，胰岛素增加和类固醇激素水平已知会增加癌症风险。鉴于美国和国外肥胖的流行不断增加，这种相关性尤为重要。但是，这些因素与肿瘤生长或癌症干细胞增殖之间的联系尚未明确定义。因此，了解正常干细胞对营养调节信号的反应的分子机制将产生对癌症生长调节的新见解。为了探索这些机制，我们使用果蝇卵巢作为模型系统来研究饮食对干细胞活性的控制。我们的实验室表明，卵巢通过改变干细胞分裂率，生殖细胞生长和卵泡细胞增殖来迅速响应饮食的变化。这个过程需要通过神经衍生的胰岛素信号直接刺激种系。来自其他实验室的最新证据表明，胰岛素对幼虫生长的影响是由埃迪酸酯（Ecdysone）抵消的，埃迪疗法是一种类固醇激素在结构和进化上与人类雌激素有关。 ecdysone在卵子发生中已知作用，包括边界细胞迁移和卵泡细胞分化的配位。另外，ecdysone信号传导的丧失可防止卵室通过卵巢生成的进展。但是，尚不清楚ecdysone信号是否连接卵子发生和饮食的速率，或者ecdysone是否调节卵巢中的胰岛素信号传导。该提案的目的是了解ecdysone和胰岛素信号传导可能会通过饮食变化来控制卵巢干细胞的机制。为了测试ecdysone信号传导调节控制卵巢对饮食反应的胰岛素途径的假设，我们将使用ecdysone途径中的功能丧失突变来确定对饮食反应中是否涉及ecdysone信号传导。我们还将确定卵巢中的哪些细胞类型接收并响应ecdysone信号。最后，我们将研究ecdysone信号传导是否可以与胰岛素对干细胞增殖速率的刺激作用进行拮抗或配合，并探测所涉及的相关机制。了解正常成年干细胞对饮食，类固醇激素和胰岛素反应的分子机制将对以支持干细胞水平的靶向癌症的开发非常有益。