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 not only trace nutrients but can be quite toxic. One mechanism of toxicity is through generation of free radicals or so-called reactive oxygen species (ROS) that have been implicated in numerous human disorders from neurodegeneration to cancer and aging to infectious disease. As part of our immune response we attack pathogens through metals and ROS, and 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 the animals the infect use weapons of metals and ROS at the host-pathogen battleground. Our current emphasis is on the Lyme disease bacterium Borrelia burdorferi and the opportunistic fungal pathogen, Candida albicans.
Research in our laboratory is focused on the understanding of molecular mechanisms that regulate the mitochondrial contribution to programmed cell death and inflammation signaling. Both processes are fundamental to a variety of diseases, including cancer, neurodegeneration and infectious diseases. In this context we are specifically interested in mitochondrial autophagy and interorganellar interactions, including with the endolysosomal compartment. We are applying a combination of fluorescence microscopy, molecular and cell biological, and biochemical approaches. Our studies aim at uncovering novel cell biological insights that can be exploited to combat diseases.
Our group studies the immunological, hormonal, and genetic factors mediating sex differences, age-related changes, and the effects of pregnancy on infectious disease pathogenesis and vaccination. Using several model systems, including influenza, Zika, and malaria, we are uncovering the mechanisms mediating how females have higher inflammatory and adaptive immune responses than males as well as how immune responses to infection or vaccination change during pregnancy and over the life course.
Laboratory of Gene Regulation
Gene regulation: Using multi-disciplinary and quantitative imaging, genomics and proteomics approaches, my lab uncovers novel roles of non-coding RNAs, non-membranous granules, and post-translational modifications.
Technology development: My lab develops proteomics and informatics tools to dissect the roles of a post-translational modification called ADP-ribosylation.
Disease focus: My lab seeks to translate our basic scientific findings to therapy, e.g., PARP inhibitor in cancers and Chikungunya viral infection.
Research in the Matunis laboratory is focused on understanding the molecular mechanisms regulating the modification of proteins by the small ubiquitin-related modifier (SUMO) and the consequences of SUMOylation in relation to protein function, cell behavior and ultimately, human disease. Particular interests include understanding how SUMOylation regulates cell cycle progression, DNA repair, nuclear import and export, and cell stress response pathways. We study SUMOylation in mammalian cells, yeast and the malaria parasite, P. facliparum using a variety of in vitro biochemical approaches, in vivo cellular approaches and genetics.
My laboratory is interested in the molecular mechanisms by which cells interpret signals from their environment that instruct them to proliferate, differentiate, or die by apoptosis. A particular focus of the lab is the regulation of NF-κB, a pleiotropic transcription factor that is required for normal innate and adaptive immunity and which is inappropriately activated in several types of human cancer.
The Sears laboratory studies how the microbiota and specific bacteria induce colon carcinogenesis. We integrate studies in humans and mouse models (including germ-free mice) employing microbiology, bioinformatics and immunologic methods to seek to achieve our goals to understand disease mechanisms and to develop new approaches to disease prevention.
The Sinnis Laboratory studies the sporozoite stage of Plasmodium, the causative agent of malaria. 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 other assays that we and others have developed, 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 two key aspects of dNTP metabolism. We are elucidating how the uniquely high concentration of dUTP in resting immune cells is used as a potent HIV-1 restriction factor in macrophages. We are also interested in the epigenetic effects of uracil when it is present in DNA. Our long-range goal is to design novel small molecules that predictably alter the make up of nucleotide pools in cells for antiviral, anticancer, and anti-inflammatory therapeutic uses.
Our laboratory is interested in investigating the signal transduction and gene regulation in bacterial infection- and genotoxic stress-associated colonic inflammation and tumorigenesis, using a combination of genetic, immunological, molecular, and cellular approaches. We are studying the molecular/cellular mechanisms and pathophysiological significance of the novel and critical pathogen-host interactions and DNA damage responses that can be mechanistically linked to colon cancer etiology in mouse and human.
My research activities focus on defining the environmental and genetic determinants of allergic airway diseases such as asthma. My lab members and I have specifically explored the role of CD4+ Th2 cells and cytokines (IL-13), and innate immune pathways (complement activation pathways, TLRs, CLRs), in the pathogenesis of asthma. I have made substantial contributions to our understanding of the molecular mechanisms underlying allergenicity of common allergens-specifically how allergens and airborne pollutants activate innate immune pathways through molecular mimicry (Nature). More recently, I have turned my attention to how the gut microbiome alters susceptibility to allergen and PM-induced asthma.