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Neurobiology toolbox for identification of lncRNA targets and associated proteins

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43MH107083-01
Agency Tracking Number: R43MH107083
Amount: $224,218.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: 104
Solicitation Number: PA14-250
Timeline
Solicitation Year: 2017
Award Year: 2015
Award Start Date (Proposal Award Date): 2015-05-01
Award End Date (Contract End Date): 2016-04-30
Small Business Information
1914 PALOMAR OAKS WAY, SUITE 150
Carlsbad, CA 92008-6509
United States
DUNS: 109145701
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 THERESA KELLY
 (323) 865-0846
 theresak@usc.edu
Business Contact
 MARY JELINEK
Phone: (760) 541-1263
Email: mjelinek@activemotif.com
Research Institution
N/A
Abstract

DESCRIPTION provided by applicant Long non coding RNAs lncRNAs have recently emerged as regulators of gene expression functioning via mechanisms that involve chromatin modification transcription and post transcriptional processing LncRNAs exceed the number protein coding genes are transcribed by the same cellular machinery and have similar structural features as messenger RNAs Recent studies have shown that correct orchestration of lncRNA expression is necessary for normal central nervous system development and their dysregulation has been implicated in the etiology of several human neurological diseases In contrast to advances in lncRNA expression profiling much less is known about their function Gaining insight into the mechanisms by which lncRNAs function requires the development of techniques that enable the identification of their genomic targets One such technique is RNA antisense purification RAP which uses a pool of overlapping antisense biotinylated probes to capture lncRNAs and the associated DNA is used to identify the genomic binding patterns Developed only recently RAP has been use to profile the genomic targets of a handful of lncRNAs in cultured cell lines This Phase I SBIR proposal intends to establish the robustness of RAP in neurobiological model systems and to assess its potential for the co incident identification of lncRNA associated proteins This would enable scientists to directly identify which lncRNAs and proteins are both present at a given genomic locus using the same technique Aim efforts will establish transfer of technical know how of using RAP to target three lncRNAs whose genomic distribution has been determined in specific cell lines Aim efforts will establish the feasibility of applying RAP to human and mouse neural cell lines and to perfused mouse brain The DNA targets of three lncRNAs known to be expressed in brain will be determined by next generation sequencing To establish whether RAP can be used to isolate and identify lncRNA associated proteins by mass spectrometry the lncRNA HOTAIR which is known to interact with the Polycomb Repressive Complex PRC will be used for proof of concept PRC is a chromatin modifying complex containing the EZH and SUZ proteins The goal of Aim is to adapt RAP to enable the successful identification of PRC constituent proteins EZH or SUZ peptides in HOTAIR containing complexes isolated by RAP Successful completion of these objectives will form the basis of future Phase II efforts where the potential of utilizing RAP in neurological systems will be further developed into a suite of enabling tools products and services that will accelerate the functional analysis of lncRNAs in the etiology of neurological behaviors and diseases The products envisioned include custom synthesis of lncRNA probe sets RAP assay kits containing a detail protocol and reagents and providing profiling of lncRNA associated proteins or targeted genomic regions as a service

PUBLIC HEALTH RELEVANCE Long non coding RNAs lncRNAs represent a new class of genes involved in regulating gene expression despite of their apparent lack of protein coding capacity Dysregulation of lncRNA expression has been associated with the development of several neurological diseases including Alzheimerandapos s and Huntingtonandapos s but little is known about how lncRNAs function This Phase I proposal describes feasibility studies for applying a newly developed technique used to determine the genomic targets of lncRNAs to neurobiology model systems which if successful will further our understanding of how lncRNAs function in the central nervous system and how their dysregulation contributes to the development of neuropathologies

* Information listed above is at the time of submission. *

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