Growing evidence indicates that extracellular microRNAs stably exist in human body fluids, including plasma, saliva, urine, and milk. Accumulating data show the presence of RNase-resistant lipid vesicles, including exosomes and apoptotic bodies. However, very little is known about the secretory machinery of microRNAs and no data have shown conclusively that microRNAs act in a cell-to-cell manner, evoking a biological outcome in a living organism. The significance of our proposal is that we aim to evaluate the functional activity of exRNA in mouse models. We describe the development of a robust and quantitative posifive readout for microRNA activity. Our plan is to use this 'pOSI-miR'technology in the most biologically relevant format- in the laboratory mouse. We combine this plafi'orm with a battery of existing exRNA microrRNA genetic knockout mouse models, teaming up with established exRNA experts to address biodistribufion, uptake, and function in target cells in primary tissues comprising all known cell types. Our plan includes studies in cell culture, using the above systems to evaluate exRNA acfivity in ES cells and in neurons. In addifion we further explore exRNA genetics using RNAi screening approaches in sensor cell lines. Finally we explore the uptake of exRNAs in a posi-sensor mouse model, laying a foundation for the development of exRNA therapeutics.

Public Health Relevance

The exploration of extracellular RNAs in mouse models is an important precept for the development of therapeutic intervention. Our study develops new technologies that promise to expedite identifying mechanisms for RNA based drug delivery.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19CA179513-01
Application #
8588508
Study Section
Special Emphasis Panel (ZRG1-OBT-S (50))
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$220,073
Indirect Cost
$87,677
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143