A defining hallmark of primary and metastatic cancers is the invasion of malignant cells through surrounding tissues. Our lab is interested in the mechanical transgression of neoplastic transformation and the underlying physics of cancer cell metastasis. Toward this end, we are applying a constellation of enabling engineering platforms, in combination with multiple (epi)genome, chemical and mechanical manipulations, to trace the evolution of biophysical events that are hardwired to local cellular motions to metastatic-invasion of cancers - at nanoscale resolution.
Currently, my laboratory focuses on the CRISPR-Cas system, a 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.
Our team is currently engaged in translational research focusing on the elucidation of pathways and mechanism by which transcription factor Nrf2 regulates the pathogenesis of inflammatory diseases.
Our research laboratory studies roles mobile DNAs play in human disease. Our group was one of the first to develop a targeted method for amplifying mobile DNA insertion sites in the human genome, and we showed that these are a significant source of structural variation. Since that time, we have continued to develop methods and reagents to characterize these understudied sequences in genomes and to understand mechanisms underlying the expression and genetic stability of interspersed repeats in normal and malignant tissues. We developed a monoclonal antibody to one of the proteins encoded for by Long INterspersed Element-1 (LINE-1) and showed its aberrant expression in a wide breadth of human cancers. We also have major projects focused on identifying functional consequences of inherited sequence variants, and exciting evidence that these predispose to cancer risk and other disease phenotypes. We use a combination of genome wide association study (GWAS) analyses, custom RNA-seq analyses, semi-high throughput gene expression reporter assays, and murine models to pursue this hypothesis.
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.
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.
Dr. Ewald has spent the past decade developing imaging, genetic, and 3D organotypic culture techniques to enable real-time analysis of cell behavior and molecular function in breast cancer. As a graduate student in Scott Fraser’s Lab at Caltech he utilized his physics training to develop and apply novel light microscopy approaches to reveal cellular interactions within intact tissues in real-time. During Dr. Ewald’s postdoctoral studies in Zena Werb’s Lab at UCSF, he developed novel 3D organotypic culture and imaging techniques to reveal the cellular mechanisms and molecular regulation of morphogenesis in primary normal and neoplastic mammary epithelia. His laboratory seeks to understand how epithelial cancer cells escape their normal developmental constraints and acquire the ability to invade and disseminate into normal tissues.
My lab is focused understanding telomerase and cellular and organismal consequences of telomere dysfunction. We use biochemistry, yeast and mice to examine telomere function. We generated telomerase null mice that are viable and show progressive telomere shortening for up to six generations. In the later generations, when telomeres are short, cells die via apoptosis or senescence. Crosses of these telomerase null mice to other tumor prone mice show that tumor formation can be greatly reduced by short telomeres. We also are using our telomerase null mice to explore the essential role of telomerase stem cell viability. Telomerase mutations cause autosomal dominant dyskeratosis congenita. People with this disease die of bone marrow failure, likely due to the stem cell loss. We have developed a mouse model to study this disease. Future work in the lab will focus on identifying genes that induce DNA damage in response to short telomeres, identifying how telomeres are processed and how telomere elongation is regulated.
The research in my program involves the development and application of molecular biomarkers of exposure, dose, and effect from environmental carcinogens. The environmental carcinogens studied include agents that are naturally occurring in the diet as well as those produced as a result of cooking practices. A major emphasis of the research has been in the elucidation of the role of aflatoxins, a common contaminate of the food supply, in the induction of liver cancer in high-risk populations living in Asia and Africa. This work has led to the identification of a very strong chemical-viral interaction between aflatoxin and the human hepatitis B virus in the induction of liver cancer. These biomarkers have also been used in many collaborative molecular epidemiology studies of liver cancer risk and recently employed to assess the efficacy of a number of chemopreventive agents in trials in high-risk aflatoxin-hepatitis B virus exposed populations. This research is now being extended to develop genetic biomarkers of p53 mutations and viral alterations in human samples as early detection of disease biomarkers using a novel mass spectroscopy based method for genotyping developed in the laboratory. Thus, the research in our laboratory focuses on the translation of mechanistic research to public health based prevention strategies.
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.
The Laiho lab seeks to understand the regulatory events that are derailed in cancers, and to detect and exploit cancer cell characteristics that could be used as basis of new cancer therapies. Our major focus is on RNA polymerase I transcription and new therapeutic agents targeting this abundantly deregulated process in cancers.
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.
Our primary research interest lies at the interface between chemistry, biology, and medicine. We employ high-throughput screening to identify modulators of various cellular processes and pathways that have been implicated in human diseases from cancer to autoimmune diseases. Once biologically active inhibitors are identified, they will serve both as probes of the biological processes of interest and as leads for the development of new drugs for treating human diseases.
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.
The Meeker laboratory is located at the Johns Hopkins University School of Medicine. Utilizing a combination of tissue-based, cell-based, and molecular approaches, our research goals focus on abnormal telomere biology as it relates to cancer initiation and tumor progression, with a particular interest in the Alternative Lengthening of Telomeres (ALT) phenotype. In addition, our laboratories focus on cancer biomarker discovery and validation with the ultimate aim to utilize these novel tissue-based biomarkers to improve individualized prevention, detection, and treatment strategies.
Dr. Pienta is involved in research to define the tumor microenvironment of prostate cancer metastases, as well as developing new therapies for prostate cancer. Current research projects in the lab are studying why prostate cancer preferentially disseminate to the bone and can remain dormant for many years before returning to a proliferative phenotype that results in metastatic disease. Additionally, his research team is looking at ways to isolate, identify, and characterize these disseminated tumor cells so that new therapies can be designed to target them prior to becoming “reactivated” and metastatic.
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.
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.
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.
My group currently focuses on identifying genetic alterations in cancer affecting sensitivity and resistance to targeted therapies, and connecting such changes to key clinical characteristics and novel therapeutic approaches. We have recently developed methods that allow non-invasive characterization of cancer, including the PARE method that provided the first whole genome analysis of tumor DNA in the circulation of cancer patients. These analyses provide a window into real-time genomic analyses of cancer patients and provide new avenues for personalized diagnostic and therapeutic intervention.
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.