NIH – The Role of Epitranscriptomics in Development and Disease (R01, R21 – Clinical Trial Not Allowed)

June 18, 2018 by School of Medicine Webmaster

Note:  the R01 version of this FOA is supported by NICHD, NCI, and NEI.  The R21 version is supported by NICHD only.  The following description is taken from the R01 version.

The purpose of this Funding Opportunity Announcement (FOA) is to encourage applications from the scientific community to support outstanding research in the area of epitranscriptomics, i.e., the chemical modifications of RNA.  Evidence is accumulating that RNA modifications regulate the function of both coding and noncoding RNAs, suggesting that these modifications are involved in both development, and in health and disease.  Yet the extent and types of these RNA modifications as well as their roles in particular biological processes remain either poorly understood or not known.  The goal of the FOA is to promote research into the role of RNA chemical modifications in the initiation and progression of various developmental processes and disease states and conditions relevant to the scientific mission of the participating ICs

Background

Chemical modifications of both DNA and protein play a crucial role in the regulation of biological processes.  For example, epigenomic marks on DNA or histones can alter gene expression and the attachment of phosphate, lipid and sugar moieties to proteins can regulate function.  RNA molecules also are subject to chemical modification; in fact, these modifications are more prevalent and diverse than DNA modifications.  More than 100 RNA modifications have been identified, with at least 60 of those being present in eukaryotic cells.  Previous biochemical studies on RNA modifications have focused on transfer and ribosomal RNAs because of their relative abundance relative to messenger RNAs (mRNAs).  However, because of the development of more sensitive detection techniques, we now know that many of the same modifications, as well as unique modifications, also occur in mRNAs and non-coding RNAs.  Evidence is accumulating that these RNA modifications are functionally significant and play important roles in a variety of biological processes and diseases in vertebrates including RNA stability, RNA-protein interactions, embryonic stem cell differentiation, development, fertility, intellectual disabilities, and the regulation of viral infection.

Epitranscriptomics is controlled by families of proteins called ‘writers’,’ readers’, and ‘erasers’; writers add a particular mark to RNA, readers translate the signal carried by the mark into a particular phenotype, and erasers remove the mark.  Even though only some of these enzymes been identified evidence is accumulating that they are critical in health and disease.  Mutations in the m5C writer Nsum2 leads to the Dubowitz-like syndrome that is characterized by multiple congenital anomalies including intellectual disability, microcephaly and impairment in growth.  ALKBH5 is a RNA demethylase important in mammalian fertility and RNA metabolism.

Research Scope

The objective of this FOA is to stimulate research into the role of epitranscriptome biology in the initiation and progression of various developmental processes, and disease states and conditions relevant to the scientific mission of the NICHD, the NCI, and the NEI.

NICHD:  Within the goals of this FOA, the NICHD is particularly interested in the following areas:

These scientific areas include, but are not limited, to:

  • Developmental Biology and Structural Variation
  • Fertility and Infertility
  • Gynecologic Health and Disease
  • Intellectual and Developmental Disabilities
  • Maternal and Pediatric Infectious Disease
  • Pregnancy and Perinatology

Additional information about scientific areas of interest for the NICHD can be viewed under the research priorities of the individual extramural scientific branches (https://www.nichd.nih.gov/about/org/der/branches).

Research topics of interest include, but are not limited to:

  • Characterization of RNA modifications and of their dynamics over the course of development or in specific disease states
  • Identification of RNAs that are modified, and the position of the modification(s).  Is there a combinatorial code for RNA modifications?
  • Identifications of the readers, writers, and erasers (RWEs) of reversible RNA modifications
  • Identification of specific substrates for RNA modifying enzymes and their changes over the course of development or in specific disease states

NCI:  Within the goals of this FOA, the NCI is particularly interested in the following areas:

Research topics of interest include, but are not limited to:

  • What are the cancer-associated alterations in readers, writers, and erasers of reversible RNA modifications?
  • What are the dynamics of the epitranscriptome over the course of cancer initiation and progression?
  • What are the specific substrates/target sites for RNA modifying enzymes and how are these altered in cancer initiation and progression?
  • What combinations of RNA modifications promote or inhibit cancer initiation and progression?
  • Can the epitranscriptome explain the discordance between tumor genomic and proteomic profiles?
  • How are the ratios of modified versus unmodified RNAs altered during cancer initiation and progression?
  • What is the subcellular localization of modified RNAs, what impact does this have on their function, and is the subcellular localization altered in cancer initiation and progression?
  • How are the stability and dynamics of RNA modifications altered during cancer initiation and progression?

NEI:  Within the goals of this FOA, the NEI is particularly interested in the following areas:

Research topics of interest include, but are not limited to:

  • Characterize and quantify all RNA modifications and their functional changes over the degenerative process or abnormal development of the eye, LGN, or visual cortex.  Using existing discovery-based high throughput methods to identify these changes is encouraged.
  • Investigate the subcellular distribution of modified RNAs and their functional relevance to ocular diseases.
  • Explore the readers, writers, and erasers that dynamically alter RNA molecules in response to environmental conditions influencing cells and circuits related to degeneration or abnormal development of the RPE, retina, optic nerve, LGN, or visual cortex.
  • Identify all RNAs that are modified and their position of the modification and the different combinations that initiate and promote degeneration of visual tissues.
  • Identify specific substrates for RNA modification enzymes associated with healthy and diseased visual tissues over time.
  • Identify changes in the epitranscriptomics that lead to visual disorders and will serve as molecular biomarkers or signatures of the disease.
  • Identify all RNA modifications that influence the physiology such as signaling pathways that regulate the development of eye tissue, the differentiation of human pluripotent stem cell, and regeneration of ocular tissues.

Topics that will not be supported by this FOA for the NICHD, the NCI and the NEI include:

  • The study of scientific research areas, and disease states and conditions not within the mission of the participating ICs.
  • Development of tools and technologies, which would include but not be limited to model systems, to promote the study of epitranscriptomics.  Developers of new tools and technologies for epitranscriptomic biology with a cancer focus should refer to RFA-CA-18-002 or PA-18-286.

Deadlines for R01s and R21s:  November 7, 2018, June 3, 2019, March 3, 2020, November 7, 2020, June 3, 2021

Filed Under: Funding Opportunities