Currently, my laboratory focuses on the CRISPR-Cas system, an RNA-based adaptive immune system found in bacteria that protects against invasion by viruses and plasmids. Mechanistic studies of the CRISPR-Cas system is contributing to ongoing efforts aimed at exploiting this system to both protect domesticated bacteria (such as those used in food and pharmaceutical production) and combat human pathogens and the spread of antibiotic resistance. Moreover, RNA-guided nucleases from the CRISPR-Cas system are currently being adapted for genome editing and regulation strategies in a wide variety of organisms, including humans. Indeed, the potential of the CRISPR-Cas toolkit is just being realized and studies centered on understanding how the CRISPR-Cas systems function represents an important need. To this end, my laboratory has provided structural and mechanistic insight into how CRISPR-Cas systems identify and destroy their DNA targets. 

We seek to understand the molecular mechanisms of macromolecular assemblies that organize, express, and preserve the cell’s genetic information. We are particularly interested in developing kinetically accurate, atomic-resolution depictions of the dynamic assemblies that control DNA replication, gene regulation, and chromosome superstructure, and in exploiting this knowledge for chemotherapeutic development.

The Cai lab focuses on understanding how the transcription process is regulated in normal and cancer cells. We are intrigued by the discoveries in our lab that many transcription factors involved in cancers can form small, liquid-like condensates in the nucleus to activate transcription. Our results are consistent with an emerging and paradigm-shifting view in biology: many biochemical reactions inside the living cell are organized in liquid-like condensates formed by weak protein and nucleic acid interactions. This implies that the material states as well as the components of cellular assemblies matter for their functions. We develop and employ many cutting-edge imaging tools in the lab, such as super resolution microscopy, single particle tracking, and optogenetics. By studying these condensates, we hope to understand how transcription is differentially organized in normal and cancer cells, and how we can target these condensates for cancer therapies.

Research in the Culotta lab focuses on the role of metal ions and oxygen radicals in biology and disease. Metal ions such as copper, iron and manganese are essential micronutrients for both microbial pathogens and their animal hosts, and during infection, a tug of war for these nutrients ensues at the host-pathogen interface. As part of our immune response, we withhold essential metals from pathogens and also bombard them with free radicals or so-called reactive oxygen species (ROS). Successful pathogens have evolved clever ways to thwart these assaults by the host. Using a combination of biochemical, cell biology, and molecular genetic approaches we are exploring how microbes and their animal hosts use weapons of metals and ROS at the infection battleground. Our current emphasis is on pathogenic fungi including the most prevalent human fungal pathogen, Candida albicans and the emerging “superbug” fungal pathogen, Candida auris.

My laboratory aims to understand the molecular mechanisms regulating eukaryotic signaling of pathways. This knowledge provides the framework needed to interpret how alterations to a pathway, such as additional proteins, mutations to pathway components, or small molecules, modulate activity and could help guide targeted therapies. To achieve this, my lab employs a multi-prong approach that combines cell-based assays, biochemistry, enzymology, biophysics, and structural biology.

Malaria, a disease caused by protozoan parasites, is one of the most dangerous infectious diseases, claiming millions of lives and infecting hundreds of millions of people annually. Malaria parasites contain an essential organelle called the apicoplast that is thought to have arisen through endosymbiosis of an algal cell which had previously incorporated a cyanobacterium. Due to its prokaryotic origin, the apicoplast contains a range of metabolic pathways that differ significantly from those of the human host. We are investigating biochemical pathways found in the apicoplast, particularly those required for the biosynthesis and modification of fatty acids. This metabolism should require several enzyme cofactors such as pantothenate, lipoic acid, biotin and iron-sulfur clusters. We are interested in these cofactors, how they are acquired, how they are used, and whether they are essential for the growth of blood stage or liver stage malaria parasites. We approach these questions with a combination of cell biology, genetic, biophysical and biochemical techniques.

The Sinnis Laboratory studies the sporozoite stage of Plasmodium, the infectious stage of the malaria parasite, inoculated by mosquitoes into the mammalian host. The impressive journey of sporozoites, from the midgut wall of the mosquito where they emerge from oocysts, to their final destination in the mammalian liver, is the major focus of our investigations. Using classic biochemistry, mutational analysis, intravital imaging, and proteomics, we aim to understand the molecular interactions between sporozoites and their mosquito and mammalian hosts that lead to the establishment of malaria infection.

My laboratory is broadly interested in how dNTP pool levels and composition influence genetic stability, adaptive and innate immunity, inflammation, carcinogenesis, cellular senescence and aging. Current work in the lab focuses on elucidating how the dNTPase and DNA/RNA binding activities of the enzyme SAMHD1 lead to HIV-1 restriction in macrophages, anticancer drug resistance, and cellular DNA repair. Our long-range goal is to design novel small molecules that inhibit or activate the various activities of SAMHD1 in cells for antiviral, anticancer, and anti-inflammatory therapeutic uses.

Dr. Wirtz studies the biophysical properties of healthy and diseased cells, including interactions between adjacent cells and the role of cellular architecture on nuclear shape and gene expression. He has developed and applied particle tracking methods to probe the micromechanical properties of living cells in normal conditions and disease state. His lab conducts groundbreaking research in the areas of cell motility, tumorigenesis and cancer metastasis, extracellular vesicles, digital pathology, machine learning applications to biological images, and immunology.