R35GM144114
Project Grant
Overview
Grant Description
Understanding the Relationship Between Codon Optimality and mRNA Stability - Project Summary
Messenger RNA transmits genetic information from DNA to protein. The regulation of mRNA levels is a fine balance between transcription rate and degradation rate. Transcriptional control is well-documented and studied. Although the major pathways in mRNA turnover have been identified, accounting for disparate half-lives has been elusive.
My lab has shown that codon optimality is a general feature that contributes greatly to mRNA stability in eukaryotes. Codon optimality reflects the disproportionate rate by which the ribosome deciphers each of the 61 codons. The randomness of tRNA selection during the mRNA decoding process manifests in codon optimality, wherein tRNA concentrations/functionality dramatically influence rate. Accordingly, codon optimality is ultimately gauged by the relative prevalence of cognate tRNAs, wherein a codon is deemed 'optimal' when tRNAs are in excess and conversely 'non-optimal' when tRNAs are more limiting. Codon optimality is also determined by the thermodynamic stability of codon/anticodon pairing.
Our major advance has been to show that the mRNA degradation machinery monitors ribosome speed and responds to degrade message when ribosome movement is relatively slow. In this proposal, we investigate how the mRNA degradation complex senses ribosome translocation rate as a function of codon optimality. We will determine the precise molecular events that occur in response to ribosome hesitations. Moreover, we focus on biological context where codon optimality is regulated both through mRNA chemical modification and tRNA regulated expression.
Lastly, the influence of codon optimality is now seen to be the major determinant of mRNA stability in yeast and in early development. Thus, work through this project has uncovered a central and critical principle in biology that contributes broadly to gene expression regulation.
Messenger RNA transmits genetic information from DNA to protein. The regulation of mRNA levels is a fine balance between transcription rate and degradation rate. Transcriptional control is well-documented and studied. Although the major pathways in mRNA turnover have been identified, accounting for disparate half-lives has been elusive.
My lab has shown that codon optimality is a general feature that contributes greatly to mRNA stability in eukaryotes. Codon optimality reflects the disproportionate rate by which the ribosome deciphers each of the 61 codons. The randomness of tRNA selection during the mRNA decoding process manifests in codon optimality, wherein tRNA concentrations/functionality dramatically influence rate. Accordingly, codon optimality is ultimately gauged by the relative prevalence of cognate tRNAs, wherein a codon is deemed 'optimal' when tRNAs are in excess and conversely 'non-optimal' when tRNAs are more limiting. Codon optimality is also determined by the thermodynamic stability of codon/anticodon pairing.
Our major advance has been to show that the mRNA degradation machinery monitors ribosome speed and responds to degrade message when ribosome movement is relatively slow. In this proposal, we investigate how the mRNA degradation complex senses ribosome translocation rate as a function of codon optimality. We will determine the precise molecular events that occur in response to ribosome hesitations. Moreover, we focus on biological context where codon optimality is regulated both through mRNA chemical modification and tRNA regulated expression.
Lastly, the influence of codon optimality is now seen to be the major determinant of mRNA stability in yeast and in early development. Thus, work through this project has uncovered a central and critical principle in biology that contributes broadly to gene expression regulation.
Awardee
Funding Goals
NOT APPLICABLE
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Baltimore,
Maryland
212051832
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 400% from $608,823 to $3,044,115.
The Johns Hopkins University was awarded
Deciphering Codon Optimality for Enhanced mRNA Stability
Project Grant R35GM144114
worth $3,044,115
from the National Institute of General Medical Sciences in June 2022 with work to be completed primarily in Baltimore Maryland United States.
The grant
has a duration of 5 years and
was awarded through assistance program 93.859 Biomedical Research and Research Training.
The Project Grant was awarded through grant opportunity Maximizing Investigators' Research Award (R35 - Clinical Trial Optional).
Status
(Ongoing)
Last Modified 6/5/26
Period of Performance
6/1/22
Start Date
5/31/27
End Date
Funding Split
$3.0M
Federal Obligation
$0.0
Non-Federal Obligation
$3.0M
Total Obligated
Activity Timeline
Transaction History
Modifications to R35GM144114
Additional Detail
Award ID FAIN
R35GM144114
SAI Number
R35GM144114-855984960
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Private Institution Of Higher Education
Awarding Office
75NS00 NIH National Institute of General Medical Sciences
Funding Office
75NS00 NIH National Institute of General Medical Sciences
Awardee UEI
FTMTDMBR29C7
Awardee CAGE
5L406
Performance District
MD-07
Senators
Benjamin Cardin
Chris Van Hollen
Chris Van Hollen
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Institute of General Medical Sciences, National Institutes of Health, Health and Human Services (075-0851) | Health research and training | Grants, subsidies, and contributions (41.0) | $1,217,646 | 100% |
Modified: 6/5/26