RNA may be extracellular (exRNA) and this diverse population of exRNA includes microRNAs, small nucleolar RNAs, piRNA, non-coding, and environmentally-derived RNAs. In humans, exRNAs are found in various body fluids, including plasma and urine. Specific exRNAs regulate key processes central to normal homeostasis and the pathogenesis of disease. Although a rapidly growing number of reports demonstrate that select exRNAs may reflect or regulate disease, a standard referent group of exRNAs has yet to be generated. In this proposal, we postulate that, in healthy adults, circulating plasma and urine levels of exRNAs;i) are associated with sex, race and ethnicity;ii) are associated with cellular gene expression;iii) may vary with age, and;iv) are associated with genomic variability. The primary goal of this RFA is the generation of exRNA profiles in healthy individuals. These profiles will both define populations and be used as a reference to facilitate disease diagnosis and discovery. To accomplish this goal several criteria are paramount, specifically;samples must;(i) come from a comprehensively characterized cohort that can accurately establish absence of disease, (ii) be racially and ethnically referent to the US population, and (iii) have genomic and phenotypic data available. Thus, we will utilize two community-based cohort studies representative of the U.S. population, the Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). exRNA will be isolated from plasma and urine from 800 study participants using an optimized non-commercial isolation method for high-yield plasma RNA extraction. We will conduct high-throughput sequencing on all 1600 samples to identify known and as-yet undiscovered circulating exRNAs. There will be a formal performance, communication, and data sharing plan and all data will be made publically available in collaboration with the ExRNA Communication Program (ERCP) Data Management &Resource Repository (DMRR). Throughout this proposal, the studies will use state-of-the art extraction techniques, new technologies, and well-defined, comprehensively characterized observational cohorts to identify exRNA from plasma and urine and determine their patterns of expression in healthy adults.
Public Health Relevance Statement: Specific RNAs found in the circulation or in bodily fluids outside of cells may regulate key processes that influence the development of disease and/or be markers of its'presence or progression. There is also known variability in RNA between individuals of different ages, sexes, races and ethnicities. Using currently available urine and plasma samples from two well-characterized observational populations, this project aims to define the expression of circulating extracellular RNAs in the US population and make these data available to other researchers and scientists.
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| Giraldez, Maria D; Spengler, Ryan M; Etheridge, Alton et al. (2018) Comprehensive multi-center assessment of small RNA-seq methods for quantitative miRNA profiling. Nat Biotechnol 36:746-757 |
| Mick, Eric; Shah, Ravi; Tanriverdi, Kahraman et al. (2017) Stroke and Circulating Extracellular RNAs. Stroke 48:828-834 |
| Clancy, Lauren; Beaulieu, Lea M; Tanriverdi, Kahraman et al. (2017) The role of RNA uptake in platelet heterogeneity. Thromb Haemost 117:948-961 |
| Clancy, Lauren; Freedman, Jane E (2016) Blood-Derived Extracellular RNA and Platelet Pathobiology: Adding Pieces to a Complex Circulating Puzzle. Circ Res 118:374-6 |
| Shah, Ravi; Tanriverdi, Kahraman; Levy, Daniel et al. (2016) Discordant Expression of Circulating microRNA from Cellular and Extracellular Sources. PLoS One 11:e0153691 |
| Freedman, Jane E; Gerstein, Mark; Mick, Eric et al. (2016) Diverse human extracellular RNAs are widely detected in human plasma. Nat Commun 7:11106 |
| Tanriverdi, Kahraman; Kucukural, Alper; Mikhalev, Ekaterina et al. (2016) Comparison of RNA isolation and associated methods for extracellular RNA detection by high-throughput quantitative polymerase chain reaction. Anal Biochem 501:66-74 |
| Shah, Ravi; Pico, Alexander R; Freedman, Jane E (2016) Translational Epidemiology: Entering a Brave New World of Team Science. Circ Res 119:1060-1062 |
| Huan, Tianxiao; Rong, Jian; Liu, Chunyu et al. (2015) Genome-wide identification of microRNA expression quantitative trait loci. Nat Commun 6:6601 |
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