RNA as a Hormone: Systemic Signaling in Mammals via Circulating, Cell-Free Small

描述(申请人提供)：这项提议寻求建立新的科学范式，即RNA分子可以作为荷尔蒙，通过血流传播到靶器官，在那里它们被吸收，并影响特定受体细胞的活动。传统的内分泌系统范式不包括作为荷尔蒙类别的RNA分子。试图建立这一范式的动机来自一系列事实：(I)RNA分子已被证明在植物中起荷尔蒙的作用，(Ii)在某些动物物种(例如蠕虫和苍蝇)中，RNA已被证明在整个有机体中传播，并将信息从一个位置携带到另一个位置，以及(Iii)我们和其他人发现，至少有一类被称为microRNAs的RNA大量存在于健康人类的血液中，特定的microRNAs在癌症等疾病状态下积累。为了建立这个新的范式，我们将专注于癌细胞分泌到血液中的microRNAs，并使用小鼠模型来确定microRNAs是否被远处的器官和组织摄取并影响。此外，我们将从血液中提纯自然状态的microRNA，并确定如果重新注入血液，它们是否可以运动到特定的靶点并具有激素样的作用。建立这一新范式不仅将对人类生理学的基本理解产生重大影响，还可能开辟基于血液中RNA激素的疾病诊断和治疗的新方法。

DESCRIPTION (provided by applicant): This proposal seeks to establish the new scientific paradigm that RNA molecules can function as hormones, traveling via the bloodstream to target organs where they are taken up and influence the activity of specific recipient cells. The conventional paradigm of the endocrine system does not include RNA molecules as a class of hormones. The motivation for trying to establish this paradigm comes from a series of facts: (i) RNA molecules have been shown to function as hormones in plants, (ii) in some animal species (e.g., worms and flies) RNA has been shown to spread throughout the organism and carry information from one site to another, and (iii) we and others have found that at least one class of RNAs, known as microRNAs, are abundantly present in the blood of healthy humans and specific microRNAs accumulate in disease states such as cancer. To establish this new paradigm, we will focus on microRNAs secreted into the blood by cancer cells and use mouse models to determine whether the microRNAs are taken up by and influence distant organs and tissues. In addition, we will purify microRNAs in their natural state from blood and determine whether if re-injected into the bloodstream they can travel to specific target sites and have a hormone-like action. Establishing this new paradigm would have a major impact not only on basic understanding of human physiology but could also open up new ways of diagnosing and treating disease based on RNA hormones in the blood.