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

描述（由申请人提供）：本提案旨在建立新的科学范式，即RNA分子可以作为激素，通过血液传播到目标器官，在那里它们被吸收并影响特定受体细胞的活性。内分泌系统的传统范式不包括RNA分子作为一类激素。试图建立这种范式的动机来自一系列事实：(1) RNA分子已被证明在植物中起激素的作用；(2)在一些动物物种（如蠕虫和苍蝇）中，RNA已被证明在整个生物体中传播，并将信息从一个部位传递到另一个部位；(3)我们和其他人发现，至少有一类RNA，即微RNA，大量存在于健康人的血液中，特定的微RNA在癌症等疾病状态中积累。为了建立这种新的范式，我们将关注癌细胞分泌到血液中的microrna，并使用小鼠模型来确定这些microrna是否被远处器官和组织吸收并影响。此外，我们将从血液中纯化自然状态的microrna，并确定如果重新注射到血液中，它们是否能到达特定的靶点，并具有类似激素的作用。建立这种新的范式不仅会对人类生理学的基本理解产生重大影响，而且还会开辟基于血液中RNA激素诊断和治疗疾病的新方法。

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.