Exosome kinetics in vivo: cell type and drug specific effects

项目摘要 外泌体已被报道为疾病和药物反应的生物标志物。它们是运输囊泡， 从细胞中分泌，并将microRNA，mRNA和蛋白质传递到其他细胞;它们可以运输摩尔- 通过血液循环将其输送到其他局部组织或远处组织。外泌体和目标 细胞含有一些表面分子（例如凝集素蛋白），这些分子似乎会影响细胞的生长速率（动力学）和生长位点。 外泌体摄取这些交付说明会因疾病或药物治疗的影响而改变，并重新 导致外泌体摄取改变。因此，了解这些变化可能会阐明新的生物标志物， 与疾病和药物反应有关。总的来说，这些数据表明，关键的未知数是 1)什么因素改变外泌体动力学和2）这些因素如何改变递送指令。在这个项目中， 我将重点了解分泌细胞的改变如何改变分泌的外泌体的动力学。 申请人的长期目标是改善外泌体生物标志物的合理使用以预测疾病， 治疗反应。了解外泌体动力学将有助于优化外泌体生物标志物valida， 这可能有助于研究设计，并可能导致阐明生物标志物相关机制的研究。 中心假设是来自不同细胞类型的分泌的外泌体具有不同的外泌体动力学， 患病和正常细胞的药物治疗改变了分泌的外泌体的动力学。目标1将 确定由不同细胞类型分泌的外来体的体内外来体动力学。目标2将决定 来源于药物处理的细胞的外来体的体内动力学参数。在完成这些研究后， Plicant希望开发识别血液中外来体动力学参数的动力学模型。K 08男人- 临床科学家研究职业发展奖详细介绍了一个为期4年的培训计划，旨在适应- plish 4主要目标：（1）学习进行体内外泌体动力学所需的技术和概念 研究和推进临床药理学领域，（2）培训先进的概念和应用 外泌体动力学参数的生物信息学和数据处理，以推进临床药理学领域， 戈伊，（3）获得将基本发现转化为合作的经验，以及（4）发展必要的专业技能- 为成功和独立的学术生涯而努力。印第安纳州大学医学院（IUSM） 承诺通过培训年轻的研究人员促进卫生研究的发展。 临床药理学部门资金充足，高度合作，在以下方面拥有强大的研究项目： 成人、儿科和产科药物遗传学、药物代谢和药物相互作用。申请人的火车- ing将包括导师和由NIH资助的具有专业知识的研究人员组成的教师咨询委员会 动力学、生物信息学、基于生理学的计算建模和循环外泌体生物学。通过 完成这K 08奖，我将制定高质量的出版物，富有成效的合作，独立 (R01)和合作研究基金与我的导师和教师顾问的反馈。

Project Summary Exosomes have been reported as biomarkers of disease and drug response. They are transport vesicles that are secreted from cells and deliver microRNAs, mRNA, and proteins to other cells; they can transport mole- cules to other local tissues, or to distant tissues through blood circulation. Both the exosomes and the target cells contain some surface molecules (e.g. lectin proteins) that appear to impact the rate (kinetics) and site of exosome uptake. These delivery instructions are changed by the effects of disease or drug treatment and re- sult in altered exosome uptake. Thus, understanding these changes may elucidate new biomarkers that are associated with both diseases and drug responses. Collectively, these data indicate that critical unknowns are 1) what factors alter exosome kinetics and 2) how do those factors alter the delivery instructions. In this project, I will focus on understanding how alterations to the secreting cells alter the kinetics of the secreted exosomes. The applicant's long-term goal is to improve the rational use of exosomal biomarkers to predict disease and treatment response. Understanding the exosome kinetics would help to optimize exosomal-biomarker valida- tion study designs and may lead to studies that elucidate the mechanisms underlying biomarker associations. The central hypothesis is that secreted exosomes from different cell types have different exosome kinetics and that the drug treatment of diseased and normal cells changes the kinetics of the secreted exosomes. Aim 1 will determine the in vivo exosome kinetics of exosomes secreted by different cell types. Aim 2 will determine the in vivo kinetic parameters of exosomes derived from drug treated cells. By completion of these studies, the ap- plicant expects to develop kinetic models that discern kinetic parameters of exosomes in blood. This K08 Men- tored Clinical Scientist Research Career Development Award details a 4-year training plan designed to accom- plish 4 main objectives: (1) learn the techniques and concepts required to conduct in vivo exosome kinetic studies and advance the field of clinical pharmacology, (2) train in the concepts and application of advanced bioinformatics and data processing of exosome kinetic parameters to advance the field of clinical pharmacolo- gy, (3) gain experience translating basic findings into collaborations, and (4) develop professional skills neces- sary for a successful and independent academic career. The Indiana University School of Medicine (IUSM) has made a commitment to promoting the growth of health research through the training of young investigators. The Division of Clinical Pharmacology is well-funded, highly collaborative, with strong research projects in adult, pediatric, and obstetric pharmacogenetics, drug metabolism, and drug interactions. The applicant's train- ing will include mentors and a faculty advisory committee consisting of NIH-funded investigators with expertise in kinetics, bioinformatics, physiologically-based computational modeling, and circulating exosome biology. By the completion of this K08 award, I will develop high-quality publications, fruitful collaborations, independent (R01) and collaborative research funding with feedback from my mentors and faculty advisors.