Oxidative stress, metabolic adaptation and therapeutic resistance of cancer:
We discovered that non small cell lung cancer frequently develop gain of function in Nrf2 due to KEAP1 mutations, which increases antioxidants and alters metabolism to drive tumor growth and cause therapeutic resistance. This has changed the paradigm in cancer biology and develop our understanding of dark side of antioxidants in cancer cells. Our current effort will help unravel mechanisms of oncogenic cooperation and metabolic adaptation using patient-derived xenografts in humanized immunocompetent mice and GEM models.
The Casero laboratory is interested in inflammation/infection-associated carcinogenesis and identifying molecular targets to be exploited in chemoprevention strategies. Spermine oxidase (SMOX) is one such target that is highly induced in several inflammatory conditions. SMOX produces DNA-damaging H2O2 and is linked to carcinogenesis. Studies are ongoing to target SMOX for chemoprevention.
My lab studies mechanisms underlying pain sensation. One focus of the lab is a group of ion channel proteins of the Transient Receptor Potential Vanilloid (TRPV) family. These channels share the intriguing feature that they can be activated by warm or painfully hot temperatures, as well as by many nonthermal stimuli. For example, TRPV1, the founding member of this family, can be activated by painful heat (>42°C), by protons, or by pungent chemicals such as capsaicin. This channel is strongly expressed in nociceptive neurons and is essential for normal behavioral responses to noxious heat. By examining these channels in recombinant and native systems, and taking advantage of knockout mice lacking one or more subtypes, we are dissecting the biological contributions of these channels to pain sensation and other processes in both neuronal and nonneuronal cells. A second focus of the lab is the use of cutting-edge molecular, cellular, genetic, behavioral and physiological approaches to understand the biological and pathophysiological basis of chronic pain in animal models and in human disease.
Chemical and biochemical approaches in the study of signal transduction, gene regulation, and metabolism.
My research focuses on the keratin filament cytoskeleton in epithelial cells with an emphasis on skin tissue. He is working to gain a better understanding of keratin genes at a mechanistic and molecular level. His laboratory discovered several novel functions for keratin proteins, including a role in regulating protein synthesis and epithelial cell growth during epithelial remodeling events. Dr. Coulombe’s research has led him to devise a therapeutic strategy for the treatment of epidermolysis bullosa simplex (EBS) and related disorders.
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.
The Drummond-Barbosa lab investigates how whole-body physiology influences the activity of tissue-resident stem cells using the Drosophila ovary system. They are currently identifying adipocyte and brain factors that contribute to the control of germline stem cells and their differentiating progeny in response to changes in diet or other stimuli.
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.
Research in the Jordan laboratory focuses on understanding the molecular mechanisms regulating DNA repair, chromosome segregation and cell cycle progression. Their lab studies the importance of Structural Maintenance of Chromosomes (SMC) complexes and cell cycle kinases, particularly Polo-like (PLK) kinases and Aurora kinases. The Jordan lab uses mouse and human pluripotent stem cells to help define the function of these proteins within essential molecular pathways of the cell. They also use mouse as a model organism to study consequences of gene mutation and chromosome missegregation, which give rise to physical and mental developmental defects, infertility and cancer predisposition. Current research from the Jordan laboratory encompasses the following:
1) Gametogenesis (spermatogenesis and oogenesis)
2) Pluripotent stem cell preservation, proliferation, and differentiation
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.
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.
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.
My research work focuses on various aspects of breast carcinogenesis, particularly the molecular and hormonal mechanisms underlying breast tumor growth, epithelial-mesenchymal transition, invasion, migration and breast cancer prevention. My studies have established important markers for development of acquired tamoxifen resistance. We are actively investigating novel molecular targets and pathways involved in chemopreventive role of bioactive components.
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.
Neurodegeneration is a poorly understood biomedical phenomenon and a major public health challenge in our increasingly aging society. Our goal is to describe at the molecular and cellular levels how specific neurons degenerate, how protein folding and misfolding operate in the cell, and how protective systems fail at disease stages.