SHAPE RNA Bioinformatics for Therapeutics and Translational Research

DESCRIPTION provided by applicant Only of the human genome is translated into proteins whereas roughly is transcribed into RNA Complex higher order structures in these RNAs fundamentally affect critical biological processes As examples RNA structures in the ribosome are the targets of many antibiotics structures in the genomes of RNA viruses like HIV and influenza are essential for viral replication and pathogenesis and roughly half of the single nucleotide polymorphisms that are most strongly associated with human diseases occur in non coding regions and likely reflect abnormal RNA structures These structures should be exploited in small molecule drug discovery efforts The Weeks laboratory has developed a chemical probing strategy called SHAPE MaP that accurately reports on RNA structure in physiologically relevant contexts Although independent groups describe SHAPE as the andquot gold standardandquot of RNA structure analysis in its current form SHAPE MaP represents a cutting edge but research grade technology This technology is based on robust chemistry and andquot digitalandquot massively parallel sequencing data and in principle could be fully automated The long term vision of Ribometrix is thus to make SHAPE MaP a platform technology with applications in drug discovery translational research and basic biological discovery In this work we will conduct proof of concept studies to solve critical bioinformatic and computational impediments to adoption by non expert laboratories via two Aims Create efficient commercial grade software for automated deconvolution of massively parallel sequencing data into quantitative validated SHAPE MaP reactivity profiles and Automate analysis pipelines to allow rapid modeling of RNA structures discovery of candidate functional motifs and quantification of ligand and drug candidate binding Progress to Phase will be justified by feasibility data showing that novice graduate student or technician level users are able to analyze and diagnose RNA structure probing experiments and identify RNA features with likely functional importance using automated error tolerant software In Phase Ribometrix will fully refine and integrate automated computational analysis to be hosted on a shared cloud computing platform and will develop efficient consulting services for pharmaceutical and academic customers and collaborators Widespread access to SHAPE technology will transform design of novel RNA based therapeutics discovery of RNA targets and analysis and validation of small molecule RNA interactions PUBLIC HEALTH RELEVANCE To explore the fundamental role of RNA in biology and to facilitate creation of RNA based and RNA directed therapeutics it is essential to understand the complex higher order structures of RNA transcripts To enable accurate analysis of RNA structure in physiologically relevant contexts Ribometrix proposes to develop a user friendly SHAPE MaP technology platform that allows novice users to implement RNA structure probing experiments and to bioinformatically interpret these experiments including large scale analyses in straightforward and quantitative ways Widespread and robust access to SHAPE technologies will transform design of mRNA and antisense therapeutics discovery of novel RNA targets and analysis and validation of small molecule RNA interactions