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.
This proposal is highly relevant to human health because it seeks to identify a new type of hormone molecule that we hypothesize carries signals throughout the human body. Establishing that RNA molecules in the blood can act as hormones could lead to better methods of diagnosing and treating a variety of human diseases.
|Chevillet, John R; Khokhlova, Tatiana D; Giraldez, Maria D et al. (2017) Release of Cell-free MicroRNA Tumor Biomarkers into the Blood Circulation with Pulsed Focused Ultrasound: A Noninvasive, Anatomically Localized, Molecular Liquid Biopsy. Radiology 283:158-167|
|Kang, Qing; Parkin, Brian; Giraldez, Maria D et al. (2016) Mutant DNA quantification by digital PCR can be confounded by heating during DNA fragmentation. Biotechniques 60:175-6, 178, 180 passim|
|Jack, Rhonda M; Grafton, Meggie M G; Rodrigues, Danika et al. (2016) Ultra-Specific Isolation of Circulating Tumor Cells Enables Rare-Cell RNA Profiling. Adv Sci (Weinh) 3:1600063|
|Johnson-Buck, Alexander; Su, Xin; Giraldez, Maria D et al. (2015) Kinetic fingerprinting to identify and count single nucleic acids. Nat Biotechnol 33:730-2|
|Zaslavsky, Alexander B; Gloeckner-Kalousek, Audrey; Adams, Mackenzie et al. (2015) Platelet-Synthesized Testosterone in Men with Prostate Cancer Induces Androgen Receptor Signaling. Neoplasia 17:490-6|
|Schummer, Michèl; Thorpe, Jason; Giraldez, Maria D et al. (2015) Evaluating Serum Markers for Hormone Receptor-Negative Breast Cancer. PLoS One 10:e0142911|
|Tewari, Muneesh (2015) A functional extracellular transcriptome in animals? Implications for biology, disease and medicine. Genome Biol 16:47|
|Nair, Viswam S; Pritchard, Colin C; Tewari, Muneesh et al. (2014) Design and Analysis for Studying microRNAs in Human Disease: A Primer on -Omic Technologies. Am J Epidemiol 180:140-52|
|Chevillet, John R; Kang, Qing; Ruf, Ingrid K et al. (2014) Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc Natl Acad Sci U S A 111:14888-93|
|Arroyo, Jason D; Gallichotte, Emily N; Tewari, Muneesh (2014) Systematic design and functional analysis of artificial microRNAs. Nucleic Acids Res 42:6064-77|
Showing the most recent 10 out of 20 publications