Stress response signaling as a metabolic sensor in reproduction

项目总结 繁殖是一个系统的决定，它依赖于营养的可获得性来支持高能量成本 配子产生和繁殖行为。与身体脂肪不足或过多相关的疾病 像神经性厌食症或多囊卵巢综合征这样的肿块与排卵减少有关，并推断- 实用程序。在人类和模式生物黑腹果蝇中，类固醇激素对于生殖是必不可少的。 尽管将营养信息传递到直接荷尔蒙功能的分子线索还没有被很好地理解。 在果蝇中，蜕皮激素受体(ECR)被类固醇激素20-羟基蜕皮酮(20E)激活。 在卵巢中等待卵母细胞成熟。有趣的是，转录因子隐头蛋白(CRC)存在于- 通过综合应激反应(ISR)途径被饥饿诱导，与ECR物理上相互作用。本研究 将研究营养感应如何通过ISR信号和类固醇激素改变生殖能力。 我最近发现，果蝇脂肪体(FB)中CRC的丢失，FB是一种类似肝脏和富含脂肪的组织， 导致卵泡死亡和脂肪/蛋黄蛋白组成下降，与20E失调有关的缺陷。 此外，ISR因子的丧失会导致成熟卵母细胞在卵巢中过度滞留。总而言之，我的数据 提示ISR信号参与了卵母细胞成熟和产卵行为的调节。在培训期间(K99) 在这个奖项的阶段，我将揭示CRC和ECR如何将代谢状态与配子发生和卵子- 产卵行为。为此，我正在与杜克大学的Kafui Dzirasa博士合作，使一种新的神经 用于果蝇的编辑工具，创建人工突触来表征ISR对产卵的调节。 饥饿激活了ISR，减弱了交配后肠道功能和求爱能力的增加 行为。在独立(R00)阶段，我将应用在 训练阶段，以确定ISR信号下游控制神经系统和 肠道起着改变生殖潜能的作用。首先，我将确定ISR如何规范女性求爱 行为，这需要中枢神经元和外周神经元的输入。接下来，我将利用这些协作 在K99阶段伪造，用于表征ECR和CRC反应的报告在整个生物体中的表达 在不同的喂养条件下，询问CRC和ECR在肠道中的作用，两者都在其中调节 干细胞动力学。这将开启关于营养感应如何控制多个生殖系统的多条线索 通过ISR信号和器官间串扰发生的事件。我提出的研究将开发新的工具和见解 这将为我的独立研究计划奠定坚实的基础，在该计划中，我将描述不同的物理量- ISR和类固醇激素信号在代谢组织中的生物学后果及其影响 行为和整个生物体生理学。最终，我的工作将揭示新陈代谢如何 控制生物的繁殖，这可能导致治疗人类新陈代谢的新疗法 导致性激素失调和不孕的紊乱。

PROJECT SUMMARY Reproduction is a systemic decision that relies on nutrient availability to support the high energetic cost of gamete production and reproductive behaviors. Disorders that correlate with insufficient or excess body fat mass like anorexia nervosa or polycystic ovarian syndrome are associated with decreased ovulation and infer- tility. In humans and the model organism Drosophila melanogaster, steroid hormones are essential for reproduc- tion, though the molecular cues that relay nutrient information to direct hormonal function are not well understood. In Drosophila, activation of Ecdysone receptor (EcR) by the steroid hormone 20-hydroxyecdysone (20E) is re- quired for oocyte maturation in the ovary. Interestingly, the transcription factor Cryptocephal (Crc), which is in- duced by starvation via the Integrated Stress Response (ISR) pathway, interacts physically with EcR. This study will examine how nutrient sensing alters reproductive capacity via ISR signaling and steroid hormones. I recently found that loss of crc in the fat body (FB), a liver-like and adipose-rich tissue in Drosophila, caused follicle death and decreased lipid/yolk protein composition, defects associated with 20E dysregulation. Additionally, loss of ISR factors caused excess retention of mature oocytes in the ovary. Together, my data suggest that ISR signaling co-regulates oocyte maturation and egg laying behavior. During the training (K99) phase of this award, I will uncover how Crc and EcR link metabolic status to gametogenesis and egg- laying behavior. To this end, I am collaborating with Dr. Kafui Dzirasa at Duke University to adapt a novel neural editing tool for use in Drosophila, creating artificial synapses to characterize regulation of egg laying by the ISR. Starvation, which activates the ISR, attenuates post-mating increases in intestinal function and courtship behavior. During the independent (R00) phase, I will apply the insights and tools acquired during the training phase to identify molecular cues downstream of ISR signaling that control nervous system and gut functions to alter reproductive potential. First, I will determine how the ISR regulates female courtship behavior, which requires inputs from central and peripheral neurons. Next, I will leverage the collaborations forged during the K99 phase to characterize organism-wide expression of EcR- and Crc-responsive reporters under different feeding conditions to interrogate the roles of Crc and EcR in the intestine, where both regulate stem cell dynamics. This will open multiple lines of inquiry into how nutrient sensing controls multiple reproductive events via ISR signaling and inter-organ crosstalk. My proposed studies will develop novel tools and insights that will lay a strong foundation for my independent research program, wherein I will characterize diverse phys- iological consequences of ISR and steroid hormone signaling in metabolic tissues and decipher how this impacts behavior and whole-organism physiology. Ultimately, my work will reveal important insights into how metabolism controls reproduction across organisms, which may lead to novel therapeutics for treating human metabolic disorders that cause sex hormone dysregulation and infertility.