Ecdysone signaling and the dietary control of oogenesis in Drosophila

描述（由申请人提供）：一些证据表明，许多癌症的生长是由一小群癌症干细胞维持的。癌症干细胞具有胚胎干细胞和成体干细胞的共同特性。事实上，细胞转化和癌症生长是由干细胞用来促进自我更新和多能性的相同的细胞-细胞通讯途径控制的。高热量饮食以及胰岛素和类固醇激素水平的增加会增加患癌症的风险。鉴于肥胖在美国和国外日益流行，这种相关性尤为重要。然而，这些因素与肿瘤生长或癌症干细胞增殖之间的关系尚未明确界定。因此，了解正常干细胞对营养调节信号作出反应的分子机制将为癌症生长的调节提供新的见解。为了探索这些机制，我们以果蝇卵巢为模型系统，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、种系细胞生长和卵泡细胞增殖，对饮食的变化做出快速反应。这一过程需要神经来源的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，蜕皮激素是一种在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起着众所周知的作用，包括协调边界细胞迁移和卵泡细胞分化。此外，蜕皮激素信号的缺失阻碍了卵黄形成过程中卵室的进展；然而，蜕皮激素信号是否与卵子发生率和饮食有关，或者蜕皮激素是否调节卵巢中的胰岛素信号，目前尚不清楚。本研究的目的是了解蜕皮激素和胰岛素信号共同作用的机制，以控制卵巢干细胞对饮食变化的反应。为了验证蜕皮激素信号调节胰岛素通路以控制卵巢对饮食反应的假设，我们将使用蜕皮激素通路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和响应蜕皮激素信号。最后，我们将探讨蜕皮激素信号是否可以拮抗或协同胰岛素对干细胞增殖速率的刺激作用，并探讨相关机制。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，将对开发针对支持干细胞水平的癌症新疗法非常有益。

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.