Muljo/Bailis

Project Title

Uncovering nutrient-specific RNA regulatory networks

NIH Mentor

Stefan A. Muljo

Penn Mentor

Will Bailis

Project Details

Circulating immune cells patrol the whole body and find themselves in starkly different metabolic environments. How these changes impact immune responses as cells move from nutrient replete blood and lymph into hypoxic and nutrient depleted inflamed tissues, or how an engineered CAR-T cell responds as it enters a tumor, is unknown. To address this, we have generated a whole transcriptome and whole translatome dataset exploring how T cells respond to acute depletion of five different metabolites. We find that these changes in metabolic context result in rapid and marked alterations in both mRNA abundance and translation of genes critical for functional immune cell programming (e.g. Tbet, Eomes, Blimp1, IFNg). Notably, we have found that the network of RNA transcripts affected are highly metabolite specific, with some primarily regulating mRNA levels and others predominantly ribosomal occupancy. We now seek to understand how these highly specific changes in mRNA networks are coordinated by RNA-binding proteins and regulatory non-coding RNA’s, such as microRNAs. Rotation students will work with the Bailis and Muljo labs to:

1) identify nutrient-sensitive RNA-binding proteins and non-coding RNAs in activated T cells;

2) generate a first-of-its-kind database of nutrient sensitive microRNAs;

3) explore how mRNA networks and dynamics are governed by these non-coding RNAs using CRISPR editing of primary T cells.

Long term the goal will be to translate these findings to improve immunotherapy by understanding how the tumor microenvironment impacts T cells through these mechanisms. Both wet-bench and bioinformatic research opportunities are available. Students will learn about the fundamentals of RNA regulation, immunometabolism, and CRISPR editing in primary T cells.