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: 7684639
• 负责人: Elizabeth Tweedie Ables
• 金额: $ 4.3万
• 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/7684639
• 关键词: Abies; Affect; Anabolism; Biological Models; Cell Communication; Cell Differentiation process; Cell Proliferation; Cells; Controlled Study; Cyst; Data; Development; Diet; Drosophila genus; Ecdysone; Embryo; Epidemic; Estrogens; Figs - dietary; Goals; Growth; Growth and Development function; Hormones; Human; Hyperinsulinism; Insulin; Insulin Receptor; Laboratories; Larva; Lead; Light; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Molecular; Normal tissue morphology; Nutrient; Nutritional; Obesity; Oocytes; Oogenesis; Ovarian; Ovary; Pathway interactions; Population; Process; Property; Receptor Signaling; Regulation; Reporter; Risk Factors; Role; Signal Pathway; Signal Transduction; Somatic Cell; Stem cells; Testing; Transforming Growth Factors; Vitellogenesis; adult stem cell; cancer risk; cancer stem cell; cancer therapy; cell growth; cell motility; cell transformation; cell type; dietary control; ecdysone receptor; egg; fly; in vivo; insight; insulin signaling; loss of function; loss of function mutation; mutant; notch protein; pluripotency; prevent; relating to nervous system; response; self-renewal; stem; stem cell division; stem cell population; steroid hormone; tumor; tumor growth

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）：多项证据表明，许多癌症的生长是由一小群癌症干细胞维持的。肿瘤干细胞具有胚胎干细胞和成体干细胞的特性。事实上，细胞转化和癌症生长是由干细胞用于促进自我更新和多能性的相同细胞-细胞通信途径控制的。高热量饮食和增加胰岛素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流行病的日益严重，这种相关性尤其重要。然而，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反应的分子机制将对癌症生长的调节产生新的见解。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。我们的实验室已经证明，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对饮食变化做出快速反应。这个过程需要神经源性胰岛素信号直接刺激生殖细胞。最近来自其他实验室的证据表明，胰岛素对幼虫生长的影响被蜕皮激素抵消，蜕皮激素是一种结构和进化上与人类雌激素相关的类固醇激素。蜕皮激素在卵子发生中具有已知的作用，包括协调边缘细胞迁移和卵泡细胞分化。此外，蜕皮激素信号的丢失阻止了卵腔通过卵黄发生的进展;然而，还不知道蜕皮激素信号是否与卵子发生和饮食的速率相关，或者蜕皮激素是否调节卵巢中的胰岛素信号。该建议的目的是了解蜕皮激素和胰岛素信号可能共同作用以控制卵巢干细胞对饮食变化的反应的机制。为了验证蜕皮激素信号调节胰岛素途径以控制卵巢对饮食的反应这一假设，我们将使用蜕皮激素途径中的功能丧失突变来确定蜕皮激素信号是否参与对饮食的反应。我们还将确定卵巢中哪些细胞类型接收并响应蜕皮激素信号。最后，我们将研究蜕皮激素信号是否可以拮抗或合作的刺激作用，胰岛素对干细胞增殖的速度，并探讨相关的机制。了解正常成体干细胞对饮食、类固醇激素和胰岛素反应的分子机制，将非常有利于开发针对支持干细胞水平的癌症新疗法。