Discovering the modification landscape of anticodon-engineered trnas and their implications for cystic fibrosis treatment
Active Project Grant Awarded Last action
- Award ID
- F31HL189215
- Recipient
-
Regents Of The University Of Michigan UEI GNJ7BBP73WE9
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $39,271
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 0% complete
- Place of performance
- Ann Arbor, MI 48109, USA
Award details come from USAspending.gov.
Description
- Abstract
- Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Premature termination codons (PTCS) lead to the synthesis of truncated, and usually nonfunctional, proteins. Approximately 10% of CF patients carry a PTC mutation, and no currently available therapeutics address these mutations. IT is believed that rescuing 15-30% of CFTR channel function would have a meaningful impact on the disease state for patients with PTC mutations. Anticodon engineered TRNAS (ACE-TRNAS) are being developed to enable an amino acid to be incorporated at a PTC. The goal of this technology is to promote the synthesis of full-length CFTR protein from a mutated gene containing a PTC. While ACE-TRNAS have been shown to work robustly in vitro, the molecular determinants that guide the efficiency and efficacy of ACE-TRNAS are not fully understood. Specifically, TRNAS are known to be highly modified biomolecules, with approximately 15% of nucleotides in each molecule modified, but the contributions (if any) of post-transcriptional modifications, which are key for canonical trna stability, folding, and transport to ACE-trna function, remain to be established. The central hypothesis of this proposal is that ACE-TRNAS will contain modifications that their canonical trna counterparts possess and that fully modified ACE-TRNAS will show the highest levels of stop codon readthrough, leading to the highest levels of functional CFTR. Additionally, IT is posited that ACE-TRNAS will harbor more modifications if delivered as cdnas as compared to those delivered as TRNAS. In specific aim 1, nanopore sequencing and mass spectrometry will be used to elucidate the modification landscape of ACE-TRNAS expressed in mammalian cells. Specific aim 2 focuses on the elucidation of the mechanistic relevance of relevant modifications using orthogonal biochemical approaches, including ribosome profiling and in vitro translation assays. This work will provide a better understanding of how the post-transcriptional status and availability of native and therapeutic TRNAS influence PTC readthrough. This information will fill critical gaps in the development of novel trna therapeutics for cystic fibrosis, as well as other genetic diseases caused by nonsense mutations. The vibrant cystic fibrosis and RNA research communities at the university of michigan will provide ample support for trainee success. Scientist training activities will extend far beyond the laboratory, including scientific communication, networking, and professional development activities, as is described in a thorough training plan.
Quick answers
Who received award F31HL189215?
F31HL189215 was awarded to Regents Of The University Of Michigan by National Heart Lung and Blood Institute (National Institutes of Health) on February 25, 2027.
How much is award F31HL189215 worth?
$39,271 has been obligated on F31HL189215.
On GovTribe
See this award's full record
- Every transaction and subaward
- The recipient's other awards and teaming partners
- Similar grant awards
- Ask GovTribe AI about this award