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.

项目概要 繁殖是一项系统性决策，依赖于营养物质的可用性来支持高能量成本 配子产生和生殖行为。与身体脂肪不足或过多相关的疾病 神经性厌食症或多囊卵巢综合征等肿块与排卵减少有关，并推断 实用性。在人类和模式生物果蝇中，类固醇激素对于生殖至关重要。 尽管将营养信息传递给直接荷尔蒙功能的分子线索尚不清楚。 在果蝇中，类固醇激素 20-羟基蜕皮激素 (20E) 会重新激活蜕皮激素受体 (EcR)。 卵巢中卵母细胞成熟所需的。有趣的是，转录因子 Cryptocephal (Crc) 饥饿通过综合应激反应 (ISR) 途径引起，与 EcR 发生物理相互作用。这项研究 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) 中的 crc 丢失，脂肪体是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，以及与 20E 失调相关的缺陷。 此外，ISR因子的丧失导致成熟卵母细胞在卵巢中过度滞留。一起，我的数据 表明 ISR 信号共同调节卵母细胞成熟和产卵行为。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联​​系起来- 铺设行为。为此，我正在与杜克大学的 Kafui Dzirasa 博士合作，采用一种新颖的神经网络 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。 饥饿会激活 ISR，减弱交配后肠道功能和求爱的增强 行为。在独立（R00）阶段，我将应用在独立期间获得的见解和工具 训练阶段识别 ISR 信号下游的分子线索，控制神经系统和 肠道功能可以改变生殖潜力。首先，我将确定 ISR 如何规范女性求爱 行为，需要来自中枢和周围神经元的输入。接下来，我将利用合作 在 K99 阶段形成，用于表征 EcR 和 Crc 响应报告基因的全生物体表达 在不同的喂养条件下探究 Crc 和 EcR 在肠道中的作用，两者都调节肠道 干细胞动力学。这将开启对营养传感如何控制多种生殖的多方面研究。 通过 ISR 信号传导和器官间串扰发生事件。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，其中我将描述不同的物理特征 ISR 和类固醇激素信号在代谢组织中的生物学后果，并解释其影响 行为和整个有机体生理学。最终，我的工作将揭示新陈代谢如何进行的重要见解 控制跨生物体的繁殖，这可能会带来治疗人类代谢的新疗法 导致性激素失调和不孕的疾病。