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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK085714-05
Application #
8542825
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (51))
Program Officer
Silva, Corinne M
Project Start
2009-09-25
Project End
2015-11-30
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$631,580
Indirect Cost
$272,728
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Cheng, Heather H; Plets, Melissa; Li, Hongli et al. (2018) Circulating microRNAs and treatment response in the Phase II SWOG S0925 study for patients with new metastatic hormone-sensitive prostate cancer. Prostate 78:121-127
Giraldez, Maria D; Chevillet, John R; Tewari, Muneesh (2018) Droplet Digital PCR for Absolute Quantification of Extracellular MicroRNAs in Plasma and Serum: Quantification of the Cancer Biomarker hsa-miR-141. Methods Mol Biol 1768:459-474
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

Showing the most recent 10 out of 22 publications