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. RNA-seq and other genome-wide RNA studies are performed in collaboration with the laboratory of Dr. Bryce Nickels, Waksman Institute, Rutgers. Also, we often uncover unexpected functions that can be better understood through x-ray crystallography or molecular modeling of the players in this process. These complementary structural studies are performed in collaboration with the laboratory of Dr. Christine Dunham, Emory University.
How ncRNAs Influence Pathogenesis – Tuberculosis as a Case Study
Tuberculosis (TB) exacts a significant, global toll on human health, accounting for more than 9 million cases of clinical disease and 1.5 million deaths in 2013. 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 and accelerate spread of the disease. Therefore, it is important to understand how latent tuberculosis develops and how it becomes reactivated because globally, the number of deaths caused by M. tuberculosis is second only to 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. Our research is the foundation for the design of improved therapeutics to treat latent TB.