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Tools for Monitoring and Manipulating Modified RNAs in the Nervous System (R43/R44)

Background
Chemical modifications play a crucial role in the regulation of biological processes.  For example, the function of a protein is often modulated by its stable tagging with phosphates, sugars, or lipids, while epigenomic marks on DNA or histones can help dial gene expression up or down.  One area that lags behind is the systematic characterization of all the chemical modifications that can befall RNA molecules (both coding and non-coding), sometimes referred to as the ?epitranscriptome.?  A few covalent RNA modifications, such as 5?mRNA capping, alternative splicing, editing, and polyadenylation, have been studied extensively, and recent evidence suggests that some RNA modifications have interesting biological and disease functions in mammals.  However, the functional roles of many other covalent RNA modifications remain poorly characterized or unknown, although they are likely to influence RNA properties and functions such as RNA stability, trafficking, localization, activity, and patterns of interactions with other molecules. 
The RNA Modification Database indicates that there are 66 known RNA modifications that occur in eukaryotic cells.  Many of these modifications occur in mammalian cells.  Transfer and ribosomal RNA have been shown to be heavily modified and some of these same modifications also occur in messenger RNA, and non-coding RNAs (including microRNAs).  With respect to brain phenotypes, some of these RNA modifications have been shown to play a role in intellectual disability, microcephaly, myoclonus epilepsy, excitotoxic cell death, depression, schizophrenia, and addiction-relevant behaviors.  For example, NSun2, an enzyme that deposits m5C on RNA, has been associated with human autosomal recessive intellectual disability and also with two additional syndromes with intellectual disability phenotypes.  Similarly, recent studies have identified N6-methyladenosine (m6A) sites in thousands of human mRNAs and suggest that this modification may play a role in regulation of alternative splicing and gene expression.  Interestingly Fat Mass and Obesity (FTO), enzymatically demethylates m6A in RNA, an activity that appears to affect dopamine function in mouse midbrain and striatum.
The major obstacles hampering our efforts to better understand RNA modifications are fundamentally technical in nature.  Presently, we lack appropriate tools and technologies for investigating the epitranscriptome broadly and at single nucleotide resolution.  This problem is compounded by the fact that the most effective and powerful assays we have today to study the transcriptome begin with a reverse transcription step that either erases the native modifications that exist on the original RNA molecule or is prematurely aborted when the reverse transcriptase encounters certain modifications.   
Research Objectives
Despite the growing interest in and importance of RNA modifications, the available tools that scientists have to monitor and manipulate modified RNAs are extremely limited.  The purpose of this initiative is to incentivize small businesses to generate tools, technologies, and products for monitoring and manipulating covalently modified eukaryotic RNA, including messenger RNA and regulatory RNA.  In the long term, it is hoped that these tools and products will serve as the foundation for NIDA-relevant research into the potential roles of RNA modifications in both HIV/AIDS infection and progression as well as into the molecular mechanisms of substance abuse disorders and co-occurring psychiatric disorders. 
Two companion FOAs have been released in this scientific area:  RFA-DA-16-006 describes the STTR R41/R42 mechanism, while this FOA (RFA-DA-16-005) describes the SBIR R43/R44 mechanism.  If the innovative tool to be commercialized will be developed via a partnership of ideas between a small business and an academic/non-profit research institution, the program director/principal investigator should consider applying using the STTR mechanism (R41/R42).  Otherwise, small businesses interested in the development of relevant innovative technologies are encouraged to apply via the SBIR mechanism (R43/R44) with this initiative.  Applicants are encouraged to contact NIH Scientific/Research staff for more detailed guidance. 
Examples of Potential Tools, Technologies, or Products.  This initiative will support small business development of research-enabling tools, technologies, or products such as (but not limited to):

Well-validated antibodies, affinity reagents, or affinity-based assay kits for detection, quantitation, or immunoprecipitation of modified RNAs, or enzymes that write, erase, or bind to these modifications.
Systems or kits that enable high-throughput mapping of specific RNA modifications to residues in individual RNA species using genome-wide sequencing approaches.  For example, this could include RNA chemical modification or targeting approaches analogous to the bisulfite sequencing assays used for detecting methylcytosine or hydroxymethylcytosine in DNA. 
Approaches that enable researchers to sequence RNA without a cDNA intermediate or that otherwise preserve or amplify the RNA modification information.  This could include the development or adaptation of nanoscale sequencing devices or other equipment for direct identification and quantitation of sequence-specific RNA modifications.
Assay systems or reagents that facilitate the discovery, detection or quantitation of modified RNAs, circular RNAs, edited RNAs, or RNA modification readers, writers, or erasers. 
Approaches that exploit the ability of certain RNA modifications to disrupt reverse transcription.
Products or systems that enable simultaneous detection of many types of RNA modifications at high sensitivity.
Assay systems or reagents that enable researchers to monitor the effect of an RNA modification on the structure or function of an individual RNA.
Products that would enable the in vitro or in vivo imaging of modified RNA molecules.
The development of analytical software tools to facilitate the identification of modified, circular, or edited RNA from high-throughput sequencing datasets.  This could include algorithms that improve our ability to identify which base on a given RNA is modified. 
The identification of small molecules that act on RNA modification readers, writers, and erasers to facilitate functional investigations. 
The development of constructs, kits, or genetic resources that enable researchers to manipulate modified RNAs to enable investigation into their biological or disease functions. 

Special Considerations
HIV/AIDS Counseling and Testing Policy for the National Institute on Drug Abuse:  In light of recent significant advances in rapid testing for HIV and in effective treatments for HIV, NIDA has revised its 2001 policy on HIV counseling and testing.  NIDA-funded researchers are strongly encouraged to provide and/or refer research subjects to HIV risk reduction education and education about the benefits of HIV treatment, counseling and testing, referral to treatment, and other appropriate interventions to prevent acquisition and transmission of HIV.  This policy applies to all NIDA funded research conducted domestically or internationally.  For more information see https://grants.nih.gov/grants/guide/notice-files/NOT-DA-07-013.html.
National Advisory Council on Drug Abuse Recommended Guidelines for the Administration of Drugs to Human Subjects:  The National Advisory Council on Drug Abuse (NACDA) recognizes the importance of research involving the administration of drugs with abuse potential, and dependence or addiction liability, to human subjects.   Potential applicants are encouraged to obtain and review these recommendations of Council before submitting an application that will administer compounds to human subjects.  The guidelines are available on NIDA’s Web site at  https://www.drugabuse.gov/funding/clinical-research/nacda-guidelines-administration-drugs-to-human-subjects.
Points to Consider Regarding Tobacco Industry Funding of NIDA Applicants: The National Advisory Council on Drug Abuse (NACDA) encourages NIDA and its grantees to consider the points it has set forth with regard to existing or prospective sponsored research agreements with tobacco companies or their related entities and the impact of acceptance of tobacco industry funding on NIDA’s credibility and reputation within the scientific community.  Please see https://www.drugabuse.gov/about-nida/advisory-boards-groups/national-advisory-council-drug-abuse-nacda/council-statements/points-to-consider-regarding- for details.
 
Data Harmonization for Substance Abuse and Addiction via the PhenX Toolkit:  NIDA strongly encourages investigators involved in human-subjects studies to employ a common set of tools and resources that will promote the collection of comparable data across studies and to do so by incorporating the measures from the Core and Specialty collections, which are available in the Substance Abuse and Addiction Collection of the PhenX Toolkit (www.phenxtoolkit.org).  Please see NOT-DA-12-008 (https://grants.nih.gov/grants/guide/notice-files/NOT-DA-12-008.html) for further details.

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