Project Leader: Zez Williams. This project addresses fundamental gaps in our knowledge of Extracellular RNAs (exRNAs) in circulation and will provide the foundation for understanding both their physiological and pathological functions as well as their potential clinical utility. We currently lack a reference profile of circulating coding and non-coding RNAs?and we lack the knowledge of the normal variability to the reference profile within a single individual over time, between similar individuals and between populations differing in gender, body mass index and age.
In Aim 1 we will generate a comprehensive and quantitative reference atlas of extracellular RNAs (exRNAs) in circulation from a few healthy individuals and examine the normal variability within an individual and between individuals based on gender, age, and BMl. This atlas will be produce utilizing RNAseq technology developed in our laboratories. This atlas will serve as a foundation for discovery of new biomarkers associated with disease and inform our understanding of potential roles for exRNA in circulation in physiology and disease. We do not understand how different cell- and tissue- types contribute to the total pool of extracellular circulating RNAs.
In Aim 2 we will determine the tissue- and cell-specific contribution to total circulating exRNA using the human placenta as a model organ and combining that information with tissue-specific RNAseq data. We will examine which tissues and RNA types contribute to the overall pool of exRNA in circulation. We do not understand the dynamics within the extracellular circulating RNA compartment?how quickly the component RNAs enter and are cleared from this space. This project seeks to systematically address these areas In Aim 3 we will determine the clearance rate and kinetics of circulating exRNA. This will be accomplished by serially monitoring the plasma and urine of women post-partum and using placenta-specific exRNAs as markers. In summary, we propose to analyze exRNAs in using RNAseq to produce a comprehensive and quantitative reference profile for single individuals over time as well as between populations and to determine the tissue- and cellular origin for these exRNAs as well as their dynamics. Collectively, these results will answer basic questions regarding the full RNA composition of serum, provide a firm foundation for future studies of exRNAs and provide important biomedical insights.
This project utilizes RNAseq technology that we have recently developed and the pregnancy model in the setting of a diverse population to comprehensively profile circulating exRNAs and capture their normal variation as well as to provide insights into the origins and dynamics the RNAs. The findings will provide the essential foundation for understanding how circulating exRNAs are formed, how they function in health and disease, and how they may be used as diagnostic and therapeutic agents
|Max, Klaas E A; Bertram, Karl; Akat, Kemal Marc et al. (2018) Human plasma and serum extracellular small RNA reference profiles and their clinical utility. Proc Natl Acad Sci U S A 115:E5334-E5343|
|Suryawanshi, Hemant; Morozov, Pavel; Straus, Alexander et al. (2018) A single-cell survey of the human first-trimester placenta and decidua. Sci Adv 4:eaau4788|
|Wei, Shan; Weiss, Zachary R; Williams, Zev (2018) Rapid Multiplex Small DNA Sequencing on the MinION Nanopore Sequencing Platform. G3 (Bethesda) 8:1649-1657|
|Gerstberger, Stefanie; Meyer, Cindy; Benjamin-Hong, Sigi et al. (2017) The Conserved RNA Exonuclease Rexo5 Is Required for 3' End Maturation of 28S rRNA, 5S rRNA, and snoRNAs. Cell Rep 21:758-772|
|Smith, Eve Mary Dorothy; Jorgensen, Andrea Lyn; Midgley, Angela et al. (2017) International validation of a urinary biomarker panel for identification of active lupus nephritis in children. Pediatr Nephrol 32:283-295|
|Gogakos, Tasos; Brown, Miguel; Garzia, Aitor et al. (2017) Characterizing Expression and Processing of Precursor and Mature Human tRNAs by Hydro-tRNAseq and PAR-CLIP. Cell Rep 20:1463-1475|
|Zheng, Luqian; Mairhofer, Elisabeth; Teplova, Marianna et al. (2017) Structure-based insights into self-cleavage by a four-way junctional twister-sister ribozyme. Nat Commun 8:1180|
|Gao, Pu; Yang, Hui; Rajashankar, Kanagalaghatta R et al. (2016) Type V CRISPR-Cas Cpf1 endonuclease employs a unique mechanism for crRNA-mediated target DNA recognition. Cell Res 26:901-13|
|Wei, Shan; Williams, Zev (2016) Rapid Short-Read Sequencing and Aneuploidy Detection Using MinION Nanopore Technology. Genetics 202:37-44|
|Ren, Aiming; Vušurovi?, Nikola; Gebetsberger, Jennifer et al. (2016) Pistol ribozyme adopts a pseudoknot fold facilitating site-specific in-line cleavage. Nat Chem Biol 12:702-8|
Showing the most recent 10 out of 23 publications