Current Funded Projects
Nucleocytoplasmic Transport – Nucleocytoplasmic transport is essential for eukaryotic cell function and plays a key role in the development of many human diseases. The nuclear translocation of critical molecules such as transcription factors, DNA replication factors, and oncogenes is increasingly recognized as an important way to regulate gene expression, cell differentiation, and transformation, making it a promising target for drug development. Early in my career, I elucidated how human importin beta recognizes classical (Cingolani et al., Nature, 1999) and non-classical (Cingolani et al., Mol Cell, 2002) import substrates. Over the past twenty years, my lab has studied how disease-related signaling molecules (e.g., NF-kB, STAT1, Hepatitis B Virus, etc.) are transported into the cell nucleus by importins, and how cellular signals regulate these complex pathways. Our long-term goal is to develop new drugs to prevent abnormal nuclear transport of signaling factors involved in cancer.
Mechanisms of TDP-43 aggregation – We are pursuing basic and translational studies on the ALS-related RNA-binding protein TDP-43 in collaboration with the labs of Dr. Lin Guo at Thomas Jefferson University and Dr. Peter King at UAB. We found that TDP-43 is imported into the nucleus by a heterodimer of importin alpha1/beta1, which recognizes an N-terminal NLS, disrupting the dimerization of the N-terminal Domain (NTD) upstream of the NLS (Doll et al., Cell Reports, 2022). Our working hypothesis is that disruption of NTD dimerization reduces TDP-43 C-terminal prion-like domain (CTD) aggregation, possibly explaining the reported chaperone-like activity of importins (Guo et al., Cell, 2018). The overarching goal of our research is to understand how TDP-43 aggregation occurs and the role of importins as cytoplasmic chaperones. We aim to develop new therapies that prevent or reduce the abnormal aggregation of TDP-43 in neurons.
Bacteriophage Structure and Genome Ejection – Bacteriophage research has experienced a renaissance over the past 20 years, with growing applications in biotechnology, the food industry, and clinics. My lab has long been interested in bacteriophage biology, especially therapeutic phages used in clinics to eliminate human pathogens. In partnership with Armata Pharmaceuticals, a leader in Phage Therapy, we are studying phage biomedicines used in ongoing clinical trials to combat infections caused by antibiotic-resistant strains of Pseudomonas aeruginosa and Staphylococcus aureus. Our main goal is to annotate de novo all phage structural proteins responsible for host adsorption and genome ejection from cryo-EM densities, and to use the knowledge gained from this structural repertoire for rational engineering of phage biomedicines. We also conduct fundamental studies on bacteriophages’ ejection proteins and the giant RNA polymerase ejected by Schitoviruses during infection. This work aims to determine how RNA transcription is coupled with genome ejection during infection.
Mycobacterium tuberculosis Virulence Factors – In collaboration with Dr. Michael Niederweis at UAB, we have studied Mycobacterium tuberculosis (MtB) virulence factors for over fifteen years. We determined the first atomic structure of the Mtb Necrotizing Toxin (TNT) in complex with the immunity factor IFT (Sun et al., Nature Struct Mol Biol, 2015). TNT hydrolyzes the essential co-enzyme nicotinamide adenine dinucleotide (NAD+) in the cytosol of Mtb-infected macrophages. More recently, we have focused on the machinery required for iron uptake in Mtb. We have determined the atomic structure of the dipeptide permease Dpp, which is essential for heme uptake across the inner membrane of Mtb (Mitra et al., Nat Commun, 2019). Our current work focuses on the discovery and structural and enzymatic analysis of MtB outer membrane proteins, which, in many cases, remain unexplored and constitute virulence factors in MtB pathogenesis.
