Research

Post-transcriptional gene regulation (PTGR) is a molecular mechanism for optimizing gene expression to meet cellular needs. The main components of this control mechanism are microRNAs (miRNAs), RNA-binding proteins (RBPs), and their target RNAs. These components are all encoded within the human genome and generated through recognized or novel molecular biogenesis pathways. PTGR mediates many physiological and developmental processes through RNA-RNA and protein-RNA interactions. Surprisingly, seemingly unrelated disease processes, such as cancer, neurodegeneration, neurodevelopmental disorders, and some infectious diseases, have defective PTGR as a common pathomechanism. Given the complexity of this regulatory mechanism and the abundance of enigmatic rare diseases, there is considerably more to learn about PTGR in health and disease.

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

 

CURRENT PROJECTS

miRNA CURATION AND EXPRESSION IN HUMAN TISSUES AND CELL LINES.

In close collaboration with the Tuschl lab, the goal of this project is to provide the miRNA research community with a list of curated miRNAs for reliable, safe, and effective miRNA diagnostics.

miRNA-GUIDED DIAGNOSTIC AND MECHANISTIC STUDIES OF NEUROENDOCRINE TUMORS.

The goals of this project are (i) to identify and validate clinically relevant miRNA biomarkers in NETs from different anatomic sites, and (ii) to evaluate the oncogenic or tumor suppressor potential of select miRNAs in neuroendocrine tumorigenesis.

miRNA-mRNA INTERACTION ANALYSES.

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

 

POTENTIAL PROJECTS

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 neurodegenerative processes, using PAR-CLIP. This project will demonstrate feasibility and allow us to investigate RBPs in other disease processes.

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 rare disease biology.

NOVEL PTGR MECHANISMS

In collaboration with investigators at the North-Eastern Federal University in the Sakha Republic and Dr. Lev Goldfarb (NIH), the goals of this project are (i) to identify disease-related variants in genes that encode the PTGR machinery, and (ii) to identify the causes of local rare diseases using RNA-guided diagnostics. This challenging project is for those with an adventurous nature.

 

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