Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY RNA modification is an emerging concept because a diverse set of modified nucleotides are found in mRNA sequences. The m6A modification is catalyzed by RNA methyltransferase complex containing METTL3 that catalyzes the addition of a methyl group at N6 position of adenosine which affects gene expression via regulation of RNA metabolism, function, and localization. N6,2’-O-dimethyladenosine (m6Am) is an abundant RNA modification located adjacent to the 5’-end of mRNA 7-methylguanosine (m7G) cap structure. Since m6Am is found at the first transcribed nucleotide in ~30% of the cellular mRNAs, m6Am can have a major influence on gene expression of the transcriptome. Human Phosphorylated CTD Interacting Factor 1 (PCIF1) as cap-specific adenosine-N6-MTase (CAPAM), that catalyzes cap-specific m6A methylation on 2’-O- methylated A at the 5’-ends of mRNAs. So far, the role of m6Am RNA modification and the catalytic function of PCIF1 in biological and disease processes, especially in regulating viral infections and host-pathogens interactions have not be determined. Despite remarkable success in treating HIV/AIDS, we do not have a functional or complete cure for the disease. The molecular networks of host cell regulating HIV-1 transcription, replication, and latency are not completely understood. The overall objective of this proposal is to delineate the molecular and cellular mechanisms by which HIV-1 (HIV) infection alters host transcriptional and translational programs. Our project has three specific aims: Aim 1: Define the dynamics and mapping of human m6Am RNA methylome by HIV infection and methamphetamine (MA) exposure. Aim 2: Determine how HIV alters m6Am methylome of host cell. Aim 3: Determine how RNA modifications influences HIV pathogenesis. Successful completion of these aims will reveal function of PCIF1, and a new regulatory mechanism involved in HIV gene expression and latency.
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