Develop genomewide technology to profile DNA ADP-ribosylation
Active Project Grant Awarded Last action
- Award ID
- R21GM154218
- Recipient
-
The Johns Hopkins University UEI FTMTDMBR29C7
- Awarding agency
-
National Institute of General Medical Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $450,313
Award facts
- Assistance listing
- 93.859 Biomedical Research and Research Training
- Completion date 72% complete
- Originally
- Funding agency
- Assistant Secretary for Financial Resources Department of Health and Human Services
- Place of performance
- Baltimore, MD 21205, USA
Award details come from USAspending.gov.
Description
- Abstract
- Our research program seeks to develop innovative technologies to investigate the role of ADP-ribosylation, an under-studied DNA modification implicated in critical biological processes, including DNA repair, genome replication, and pathogen defense. Though prevalent across all kingdoms of life, from bacteria to humans, the precise function and extent of DNA ADP-ribosylation remain elusive. Current knowledge largely stems from studies on the bacterial dart-darg toxin-antitoxin system, and more recently, the discoveries of DNA modification by the anticancer drug target PARP1 in human cells. One significant challenge in the field is the absence of technology capable of identifying DNA ADP-ribosylation sites across the whole genome. Past efforts have involved meticulous mutagenesis using radioactive labeling on predefined oligo sequences or breaking down the genome to individual bases for modification assessment. However, these methods are limited in their ability to provide the broader genomic context of DNA ADP-ribosylation. Our goal is to bridge this GAP through the development of two complementary techniques, using the well- characterized dart-mediated ADP-ribosylation as our model. The first repurposes tools we have developed to study protein ADP-ribosylation and applies them to DNA, using high-throughput illumina-based sequencing to pinpoint the modification site. The second approach involves nanopore sequencing, using a modified transmembrane protein as both a channel for DNA passage and a biosensor for base identification. By monitoring changes in electric current, we can distinguish specific bases and detect DNA modifications. To optimize this method, we will collaborate with leading nanopore epigenetics expert DR. Winston timp at hopkins and adapt established machine learning approaches for electric current data analyses. We will test and refine our methods using dart-modified oligos with defined sequences and genomic DNA standards. In summary, this program aims to unravel the complexities of DNA ADP-ribosylation using cutting-edge sequencing methods. These strategies will enable the investigation of the sequence context of ADP- ribosylation sites and, in due course (beyond the current scope), the study of motifs from diverse pathogen toxins and other modifying enzymes such as human parps. By developing tools to reveal the mechanisms of DNA repair, gene regulation, and pathogen defense, we anticipate that our work may catalyze significant advancements in healthcare, potentially leading to the development of new treatment and detection tools for a range of diseases, from infections to cancers.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $245,625 | |
| Original award | $204,688 |
Quick answers
Who received award R21GM154218?
R21GM154218 was awarded to The Johns Hopkins University by National Institute of General Medical Sciences (National Institutes of Health) on September 1, 2024.
How much is award R21GM154218 worth?
$450,313 has been obligated on R21GM154218.
Which agency awarded R21GM154218?
National Institute of General Medical Sciences (National Institutes of Health) awarded R21GM154218, with funding from Assistant Secretary for Financial Resources (Department of Health and Human Services).
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