Determining the mechanisms of selective miRNA packaging for extracellular miRNA secretion in prostate cancer

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 DESCRIPTION (provided by applicant): MicroRNAs are short noncoding RNAs that function as powerful regulators of gene networks. Although they were classically thought to function only within the cell, strikingly stable populations of extracellular microRNAs (ex-miRNAs) have been discovered in a variety of body fluids. Because their profile in serum is altered in many cancers such as prostate cancer, ex-miRNAs hold promise as a tool for cancer detection and treatment prognosis. Additionally, many studies are revealing a possible biological utility for ex- miRNAs shuttled between cells in extracellular vesicles, called exosomes, as mediators of paracrine signaling. Despite growing interest in the function of secreted ex-miRNAs and their clinical application as biomarkers for cancer, we still lack understanding of the underlying mechanisms of ex-miRNA packaging and secretion. The overall goal of this proposal is to identify the steps of selection for miRNAs during packaging and secretion via exosomes and determine how oncogenic stimuli can affect these mechanisms. I hypothesize that selective miRNA secretion is controlled by selective multivesicular body release and mechanisms of intraluminal vesicle formation, both of which are modulated by oncogenic signaling. These studies will shed light on the biological implication of ex-miRNAs in paracrine signaling and further our understanding of how to utilize them as novel biomarkers for cancer. This research project is crafted to facilitate my development into a versatile scientist capable of becoming a leader in academia. To achieve this goal, my training plan will help me advance my skills in biochemistry, molecular biology, and bioinformatics. My instruction will also be supported by coursework in cancer biology, ethics, and statistics/data analysis. I will further my career development by improving my communication and writing skills directly from my sponsor and other mentors, as well as taking advantage of classes and seminars offered at UCSF. The resources and mentorship afforded to me in this setting will give me the best opportunity to achieve my goal of leading an independent laboratory in the future.