Stress response signaling as a metabolic sensor in reproduction

应激反应信号作为生殖中的代谢传感器

• 批准号: 10644353
• 负责人: Lydia Grmai
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644353
• 关键词: Address; Adipose tissue; Anorexia Nervosa; Attenuated; Award; Behavior; Behavioral; Biochemical; Body fat; Brain; Cells; Cellular Stress; Cessation of life; Collaborations; Courtship; Cues; Data; Defect; Deposition; Disease; Drosophila genus; Drosophila melanogaster; Ecdysone; Ecdysterone; Egg Yolk Proteins; Endowment; Energy Metabolism; Event; Fat Body; Female; Fertility; Foundations; Gametogenesis; Genetic; Genetic Transcription; Germ Cells; Gonadal Steroid Hormones; Gonadal structure; Graafian Follicles; Homeostasis; Hormonal; Hormones; Human; Infertility; Intestines; Laser Scanning Confocal Microscopy; Link; Lipids; Liver; Mentors; Metabolic; Metabolic Diseases; Metabolism; Methods; Molecular; Nervous System control; Neurons; Neuropeptides; Neurosciences; Nutrient; Nutrient availability; Nutritional; Nutritional status; Oocytes; Oogenesis; Organ; Organism; Ovary; Ovulation; Partner in relationship; Pathway interactions; Peripheral; Phase; Physiological; Physiology; Polycystic Ovary Syndrome; Process; Production; Protein Biosynthesis; Proteins; Regulation; Reporter; Reproduction; Reproductive Behavior; Research; Research Personnel; Resource Allocation; Role; Sense Organs; Signal Pathway; Signal Transduction; Site; Starvation; Stress; Stress Response Signaling; Synapses; System; Techniques; Testing; Tissues; Training; Universities; Whole Organism; Work; biological adaptation to stress; cost; detection of nutrient; ecdysone receptor; egg; feeding; fitness; forging; hormonal signals; insight; intestinal homeostasis; mind control; model organism; neural; neuronal circuitry; neuroregulation; novel; novel therapeutics; nutrient deprivation; nutrition; offspring; oocyte maturation; programs; receptor; reproductive; response; sensor; stem cells; steroid hormone; steroid hormone receptor; tool; transcription factor

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.

项目摘要 繁殖是一个系统性的决定，它依赖于营养的可用性来支持高能量成本 配子的产生和繁殖行为。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， tility。在人类和模式生物黑腹果蝇中，类固醇激素对生殖是必不可少的， 然而，将营养信息传递到直接激素功能的分子线索还没有得到很好的理解。 在果蝇中，类固醇激素20-羟基蜕皮激素（20 E）对蜕皮激素受体（EcR）的激活被重新激活。 卵母细胞在卵巢中成熟所需的。有趣的是，转录因子Cryptocephal（Crc），这是在- 通过综合应激反应（ISR）途径由饥饿诱导的EcR与EcR物理相互作用。本研究 将研究营养传感如何通过ISR信号和类固醇激素改变生殖能力。 我最近发现，在果蝇的脂肪体（FB）中，一种类似肝脏且富含脂肪的组织， 导致卵泡死亡和脂质/卵黄蛋白组成减少，缺陷与20 E失调。 此外，ISR因子的丢失导致卵巢中成熟卵母细胞的过度保留。我的数据 表明ISR信号共调节卵母细胞成熟和产卵行为。培训期间（K99） 在这个奖项的第一阶段，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 Djanasa博士合作， 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ISR，减弱交配后肠道功能和求偶的增加 行为在独立（R 00）阶段，我将应用在 训练阶段，以识别控制神经系统的ISR信号传导下游的分子线索， 肠道功能改变生殖潜力。首先，我将确定ISR如何调节女性求爱 行为，这需要来自中枢和外周神经元的输入。接下来，我将利用 在K99阶段形成，以表征EcR和Crc应答报告基因的生物体范围内表达 在不同的喂养条件下，询问Crc和EcR在肠道中的作用， 干细胞动力学这将开启多条调查路线，了解营养感测如何控制多种生殖 事件通过ISR信号和器官间串扰。我提议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，其中我将描述不同的物理- 代谢组织中ISR和类固醇激素信号传导的生物学后果，并解释其如何影响 行为和整体生物生理学。最终，我的工作将揭示新陈代谢如何 控制生物体的繁殖，这可能会导致治疗人类代谢的新疗法。 导致性激素失调和不育的疾病。