Research

microRNA-mediated gene regulation is a molecular mechanism for optimizing gene expression during many cellular processes. microRNAs are small (19-24 nucleotide) RNA molecules that negatively regulate gene expression. Although these molecules are encoded in the human genome, microRNAs are typically cleaved from longer precursor RNA molecules by enzymes in the nucleus and cytoplasm, before targeting messenger RNA molecules on a cytoplasmic protein scaffold. microRNAs regulate many physiological and developmental processes. Surprisingly, many disease processes, such as cancer, neurodegeneration, and some infections, share defective microRNA-mediated gene regulation as a pathomechanism. Given the complexity of this genetic regulatory mechanisms, there is considerably more to learn about this type of gene regulation in health and disease.

We investigate and study microRNA-mediated gene regulation using clinical materials and relevant cell culture and/or animal models, respectively. As translational researchers, we start our investigations using molecular analyses of relevant clinical samples and move into model systems after generating realistic hypotheses. To study microRNA-mediate gene regulation, we use a number of techniques that I learned or co-developed while training in the Tuschl lab at The Rockefeller University including: barcoded small RNA sequencing, RNA seq, nested multiplex PCR with barcoded pyrosequencing, PAR-CLIP, and EMSAs. We incorporate nucleic acid chemistry and computational biology approaches as required and recently added lentiviral overexpression and CRISPR/Cas9 genome editing to our experimental tool kit.

CURRENT PROJECTS

microRNA SEQUENCE ANNOTATION AND EXPRESSION IN HUMAN TISSUES, CELL LINES, AND BODY FLUIDS

In close collaboration with the Tuschl lab at The Rockefeller University, the goal of this project is to provide the microRNA research community with an accurate list of curated human microRNAs for reliable, safe, and effective microRNA-guided diagnostics and therapeutics

microRNA-GUIDED DIAGNOSTIC AND MECHANISTIC STUDIES OF NEUROENDOCRINE TUMORS

The goals of this project are to (i) identify and validate clinically relevant microRNA biomarkers in tissue and plasma samples from people with neuroendocrine tumors from different anatomic sites, and (ii) evaluate the oncogenic or tumor suppressor potential of select microRNAs in neuroendocrine tumorigenesis

microRNA-MESSENGER RNA INTERACTION ANALYSES

The goal of this project is to develop a computational pipeline to define and rank microRNA-messenger RNA interaction networks using paired microRNA and messenger RNA sequencing data sets. This computational project integrates very nicely with Dr. Kathrin Tyryshkin’s research program on “big data” analyses (see Team).

POTENTIAL PROJECTS

NOVEL microRNA-MEDIATED PATHOMECHANISMS

In collaboration with investigators at the NIH (Dr. Lev Goldfarb) and the North-Eastern Federal University in the Sakha Republic (Dr. Fyodor Platonov, Dr. Vsevelod Vladimirtsev, Dr. Nadezda Maksimova, Dr. Tatiana Nikolaeva), the goal of this project is to identify disease-related variants in microRNA processing enzymes, genes, and target sites. This challenging project is for those with an adventurous nature.

RNA-GUIDED DIAGNOSTICS FOR RARE DISEASES

As Director of Postgraduate Pathology Research, I encourage interested residents and trainees to make use of our expertise in RNA profiling in fresh or archived, solid or liquid clinical samples to look for causative or mechanistically important RNAs to advance our understanding of disease biology. Although we do study common diseases, we have found that rare diseases are high yield in terms of discovery.

DEFINING THE RNA TARGETS OF TDP-43

The goal of this project is to identify the RNA targets of TDP-43, an RBP that is involved in many cellular processes, using PAR-CLIP. This project will demonstrate feasibility and allow us to investigate RBPs in other disease processes.