EAGER: RUI: Elucidating the role of exosomes in the regulation of steroidogenesis

EAGER：RUI：阐明外泌体在类固醇生成调节中的作用

• 批准号: 2221192
• 负责人: Bobby Fokidis
• 金额: $ 26.08万
• 依托单位: Rollins College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2221192&HistoricalAwards=false
• 关键词: EAGER; RUI; Elucidating; role; exosomes

Exosomes are recently discovered small membrane-bound particles that are secreted into blood by cells, carrying biomolecules that may reprogram recipient cells and initiate new functions. Despite biomedical interest in exosomes as biomarkers and therapeutics, their natural physiological function remains unknown. This research explores one potential role of exosomes, as communication links between endocrine glands (the adrenal glands, ovaries, and testes) and other tissues or organs which can only synthesize hormones under certain circumstances. Using newly developed methods, this project will determine whether exosomes originating from endocrine cells carry the necessary biochemical information to initiate local steroid hormone production in non-endocrine organs, in a lizard model. Such location shifts in hormone production are observed in many biological processes, including prostate cancer, menopause, immune cell development, and non-breeding aggression in animals. This research may provide a unifying mechanism for these diverse processes, while also serving as the foundation for the interdisciplinary training of several undergraduate students, including those from traditionally underrepresented groups. The project will also support development of hands-on activities in undergraduate laboratory courses, impacting more students. Through student training and collaborations, this research will likely lead to new insights and future investigations on the hidden roles that exosomes play in hormonal function, animal physiology, and behavior.Exosomes are nanosized vesicles secreted into plasma that carry nucleic acids and other molecules that can alter phenotypes of recipient cells, but their intrinsic organismal functions remain unstudied and unknown. This research tests the hypothesis that exosomes are involved in the regulation of local steroid hormone synthesis, which occurs when “non-endocrine” tissues (e.g., liver, intestine) synthesize bioactive steroids, with exosomes serving to transfer necessary steroidogenic enzyme mRNA from endocrine glands to initiate the process. Using the Anolis lizard model system, this research will test if exosomes are necessary for both extra-adrenal glucocorticoid hormone synthesis and extra-gonadal synthesis of sex steroid hormones. This study first aims to determine if local steroidogenesis increases plasma exosome secretion using nanoparticle tracking analysis. The second aim will document if plasma exosomes contain steroidogenic enzyme mRNA using RT-PCR with targeted primers. The third aim will use a new pharmacological agent to block exosome secretion to test its necessity for local steroidogenesis. Using novel techniques and testing paradigms, a unifying and ubiquitous mechanism for activating steroidogenic machinery in non-endocrine tissues will be tested. The transfer of mRNA between tissues via exosomes to regulate physiological functions and behavior will transform current understanding of cell-to-cell communication, with implications for many fields of biology. This project also serves to provide scientific training for young biologists, including those from underrepresented groups, and will doubtlessly lead to collaborations and new biological questions on the role of exosomes in steroid-regulated functions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

外泌体最近被发现的小膜结合的颗粒被细胞分泌到血液中，携带可能重新编程受体细胞并启动新功能的生物分子。尽管对外泌体作为生物标志物和治疗的生物医学兴趣，但它们的自然生理功能仍然未知。这项研究探讨了外泌体的一个潜在作用，因为内分泌网格（肾上腺电网，卵巢和睾丸）与其他组织或器官之间的通信联系只能在某些情况下综合马匹。使用新开发的方法，该项目将确定源自内分泌细胞的外泌体是否携带必要的生化信息，以在蜥蜴模型中启动非内分泌器官中局部类固醇的果蝇生产。在许多生物学过程中观察到骑马产量的这种位置变化，包括前列腺癌，更年期，免疫细胞发育以及动物中非繁殖的侵略性。这项研究可能为这些不同的过程提供了统一的机制，同时也是对几个本科生跨学科培训的基础，包括传统上代表性不足的群体。该项目还将支持在本科实验室课程中开发动手活动，从而影响更多的学生。通过学生的培训和合作，这项研究可能会导致对外泌体在骑马功能，动物生理学和行为中发挥的隐藏作用的新见解和未来的调查。陈述是将纳米蔬菜分泌到血浆中，将核酸和其他可以改变受体型细胞的核酸和其他分子，但它们的内在功能仍然不知所措，并且是不知情的，并且不知不觉地不知所措。这项研究检验了以下假设：当局部类固醇马替酮合成的调节中，这种假说发生在“非内分泌”组织（例如肝脏，肠道）合成生物活性类固醇的情况下，外异构体的外来体可将必要的类固醇激素酶mRNA从内分蛋白中转移到内分泌网格中。使用Anolis蜥蜴模型系统，这项研究将测试是否需要外泌体对于性类固醇骑马的肾上腺外糖皮质激素马酮合成和甲状腺外合成。这项研究首先旨在确定局部类固醇生成是否使用纳米颗粒跟踪分析增加了血浆外泌体的分泌。第二个目标将记录血浆外泌体是否含有类固醇生成酶mRNA，并使用带有靶向引物的RT-PCR。第三个目标将使用新的药理学剂来阻止外泌体秘密来测试其对局部类固醇生成所需的必要条件。使用新颖的技术和测试范例，将测试一种激活非内分泌组织中类固醇生成机制的统一和无处不在的机制。通过外泌体之间的mRNA在组织之间转移以调节物理功能和行为，将改变当前对细胞对细胞通信的理解，对许多生物学领域的影响。 This project also serves to provide scientific training for young biologists, including those from underrepresented groups, and will doubtlessly lead to collaborations and new biologic questions on the role of exosomes in steroid-regulated functions.This award reflects NSF's statutory mission and Has been deemed worthwhile of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.