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

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1-GGG-A (51))
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Srinivas, Pothur R
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University of Massachusetts Medical School Worcester
Internal Medicine/Medicine
Schools of Medicine
United States
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