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

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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.