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

 描述（由申请人提供）：MicroRNA是短的非编码RNA，作为基因网络的强大调控因子发挥作用。虽然它们被经典地认为仅在细胞内起作用，但在各种体液中发现了惊人稳定的细胞外microRNA（ex-miRNAs）群体。由于它们在血清中的分布在许多癌症如前列腺癌中改变，因此前-miRNA有望作为癌症检测和治疗预后的工具。此外，许多研究揭示了在细胞外囊泡（称为外泌体）中穿梭于细胞之间的ex-miRNA作为旁分泌信号传导的介质的可能生物学效用。尽管人们对分泌的ex-miRNA的功能及其作为癌症生物标志物的临床应用越来越感兴趣，但我们仍然缺乏对ex-miRNA包装和分泌的潜在机制的理解。该提案的总体目标是确定通过外泌体包装和分泌期间选择miRNA的步骤，并确定致癌刺激如何影响这些机制。我假设选择性的miRNA分泌是由选择性的多泡体释放和腔内囊泡形成机制控制的，这两者都是由致癌信号调节的。这些研究将阐明ex-miRNAs在旁分泌信号传导中的生物学意义，并进一步了解如何利用它们作为癌症的新生物标志物。这个研究项目是精心制作的，以促进我发展成为一个多才多艺的科学家，能够成为学术界的领导者。为了实现这个目标，我的培训计划将帮助我提高我在生物化学，分子生物学和生物信息学方面的技能。我的指导也将得到癌症生物学，伦理学和统计/数据分析课程的支持。我将通过直接从我的赞助商和其他导师那里提高我的沟通和写作技巧，以及利用加州大学旧金山分校提供的课程和研讨会来进一步发展我的职业生涯。在这个环境中提供给我的资源和指导将给我最好的机会来实现我的目标，在未来领导一个独立的实验室。

 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.