Research

Non-coding RNAs and human disease

The study of RNA has evolved far beyond the mRNAs that are translated into proteins. Several other non-coding (nc) RNAs—e.g. microRNAs (miRNAs), long non-coding RNAs (lncRNAs), small interfering RNA (siRNA) among others—have now taken over the limelight. Even tRNAs, once thought to simply function in the transfer of amino acids to the growing protein chain, are emerging as a major source of non-coding RNAs that are implicated in cancer, pathological stress injuries, bacterial pathogenesis and neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS, aka Lou Gehrig's disease) and Parkinson’s Disease.

We study how posttranscriptional changes in ncRNA levels or precise alterations in ncRNAs influence cellular physiology. At the molecular level, these changes are implicated in many important processes such as stress resistance, cell survival, apoptosis, cell signaling, RNAi and protein synthesis. Manifestation of these changes is implicated in several human diseases and can also accelerate the virulence of bacterial pathogens and viruses.

Our laboratory uses state-of-the-art, genome-scale methods such as a specialized RNA-seq method and ribosomal profiling to identify which RNAs are altered in conditions that mimic diseases. We then use a spectrum of molecular approaches to pinpoint how the RNAs identified in our genome-wide methods cause disease.

How ncRNAs influence pathogenesis – tuberculosis as a case study

Tuberculosis (TB) exacts a significant, global toll on human health, accounting for an estimated 10 million cases of clinical disease and 1.6 million deaths in 2018. Infections by the causative agent, Mycobacterium tuberculosis, has the unique ability to evade being killed by our immune system and is able to persist for long periods of time as a latent infection. Latent infections can be reactivated—especially in the immune compromised—to the highly contagious, active form of TB. Therefore, it is important to understand how latent tuberculosis develops and how it gets reactivated because globally the number of deaths caused by M. tuberculosis now exceeds those caused by the HIV/AIDS virus.

We are studying the molecular switches, often in ncRNAs, that trigger the changes in M. tuberculosis that are suspected to lead to latent infection. This work is performed in collaboration with the laboratory of physician-scientist Dr. Robert Husson at Boston Children's Hospital/Harvard Medical School. These studies are designed to provide a framework for the design of new and improved therapeutics to more rapidly clear latent TB infection or prevent latent TB reactivation to active TB infection.

How ncRNAs subvert antibiotic efficacy against bacterial pathogens that plague cystic fibrosis patients

Cystic fibrosis (CF) patients are at high risk for acquiring chronic bacterial lung infections that can lead to progressive lung damage and respiratory failure. These bacterial pathogens exact a high toll on cystic fibrosis patients due to the failure of antimicrobial treatment. Some of these infections are so intractable in CF patients that they require a lung transplant, or die, despite undergoing a grueling 1-2 year course of antibiotic treatment.

We are studying why antibiotic treatment of life-threatening lung infections caused by these opportunistic bacterial pathogens so often fails in CF patients and other immune compromised individuals. Studying the mechanisms of antimicrobial resistance in these bacterial pathogens should enable the development of better biomarkers to predict the tenacity of these lung infections and set the stage for intelligent design of novel, and more effective, treatment options.