Fast-Track proposals will not be accepted.
Direct-to-Phase II will not be accepted.
Number of anticipated awards: 3-5
Budget (total costs, per award):
Phase I: $250,000 for 9 months;
Phase II: $1,500,000 for 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Chemical modifications play a crucial role in the regulation of biological processes. Protein function is often modulated by tagging with phosphates, sugars, or lipids, while epigenomic marks on DNA or histones can regulate gene expression up or down. One area that lags behind is the mechanistic understanding of the role of RNA chemical modifications, sometimes referred to as the ‘epitranscriptome’.
The RNA Modification Database lists more than 60 RNA modifications that occur in eukaryotic 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. However, the vast majority of these modifications have not been well-studied in messenger and non-coding RNAs. Even though much about RNA modifications remains to be elucidated, there is emerging evidence that RNA modifications are functionally significant and play important roles in biological processes and diseases in vertebrates.
Several RNA chemical modifications or the enzymes that catalyze the addition of modifications (writers), the removal of modifications (erasers), or translate the effects of modifications (readers) have been associated with a variety of cancers. For example, certain mutations in the N6-methyladenosine (m6A) demethylase (or ‘eraser’) FTO are associated with melanoma and breast cancer risk. Additionally, mutations in the pseudouridine ‘writer’ DKC1 cause dyskeratosis congenita, a disease associated with premature aging and increased tumor susceptibility. Furthermore, specific DKC1 mutations have been identified in human pituitary adenomas.
These early findings linking the disruption of RNA modifications to cancer initiation and progression highlight the potential importance of the field of epitranscriptomics to understanding cancer biology. However, a lack of experimental tools for monitoring RNA modifications has slowed the potential progress. The purpose of this topic is to incentivize small businesses to generate tools and technologies for monitoring covalently modified eukaryotic RNA.
The major obstacles hampering 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. Additionally, there is evidence that the availability of tools will drive research in this field. For example, an antibody-based assay for monitoring the m6A modification was developed in 2012, and by 2014 there had been a four-fold increase in the number of m6A publications.
Despite the growing interest in and importance of RNA modifications, the available tools that scientists have to monitor modified RNAs are limited. The purpose of this contract topic is to incentivize small businesses to generate tools, technologies, and products for monitoring covalently modified eukaryotic RNA, including messenger RNA and regulatory RNA. In the long term, these tools and products will allow the investigation of how altered RNA modifications contribute to the initiation and progression of cancer and potentially identify a new class of cancer biomarkers.
Potential tools, technologies, or products would include, but are not limited to:
The goal of Phase I is to develop proof-of-concept or prototype tools, technologies, or products for monitoring specific RNA modification(s). Activities and deliverables include:
The goal of Phase II is an optimized commercial resource, product, reagent, kit, or device for monitoring specific RNA modification(s).
Decisions for continued product development into Phase II will be based on:
Deliverables and activities include: