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 繁殖是一个系统性决定，依赖于营养的可用性来支持高能成本 配子生产和生殖行为。与不足或多余的身体脂肪相关的疾病 像神经性厌食症或多囊性卵巢综合征等质量与排卵和下降有关 能力。在人类和模型有机体果蝇中，类固醇激素对于再生产 尽管尚不清楚将养分信息传达到直接激素功能的分子提示。 在果蝇中，类固醇激素20-羟基甲酮（20E）激活ecdysone受体（ECR） 卵巢中的卵母细胞成熟。有趣的是，转录因子加密脑（CRC），这是In- 通过饥饿通过综合应力响应（ISR）途径引起的，与ECR物理相互作用。这项研究 将研究营养感应如何通过ISR信号传导和类固醇激素来改变生殖能力。 我最近发现，脂肪体（FB）中CRC的损失，果蝇中的肝状和富含脂肪的组织， 导致卵泡死亡和脂质/蛋黄蛋白组成减少，与20E失调相关的缺陷。 另外，ISR因子的丧失导致卵巢中成熟卵母细胞的过量保留。在一起，我的数据 表明ISR信号传导共同调节卵母细胞的成熟和卵铺卵行为。在培训期间（K99） 该奖项的阶段，我将发现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，以适应一种新颖的神经 用于果蝇中的编辑工具，创建人工突触以表征ISR对产卵的调节。 激活ISR的饥饿会减弱肠道功能和求爱的术后交配增加 行为。在独立（R00）阶段，我将应用在此期间获得的见解和工具 训练阶段以识别控制神经系统和 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，需要来自中央和周围神经元的输入。接下来，我将利用合作 在K99阶段伪造，以表征ECR和CRC响应记者的整个生物体表达 在不同的喂养条件下，询问CRC和ECR在肠中的作用，这两者都调节 干细胞动力学。这将为营养传感如何控制多种生殖，开放多种询问 通过ISR信号传导和器官间串扰的事件。我提出的研究将开发新颖的工具和见解 这将为我的独立研究计划奠定坚实的基础，其中我将表征各种各样的物理 代谢组织中ISR和类固醇激素信号传导的生物学后果，并破译这如何影响 行为和全生理学。最终，我的工作将揭示有关新陈代谢的重要见解 控制跨生物体的繁殖，这可能导致新的治疗人类代谢的治疗疗法 引起性激素失调和不育的疾病。