Research in the Photini Sinnis Lab explores the fundamental biology of the pre-erythrocytic stages of malaria. Our team is focused on the sporozoite stage of Plasmodium, which is the infective stage of the malaria parasite, and the liver stages into which they develop. We use classic biochemistry, mutational analysis, and in vitro and in vivo assays to better understand the molecular interactions between the parasite and its mosquito and mammalian hosts. Our goal is to translate our findings to help develop treatments and a vaccine that target the malaria parasite.

The long-term goal of the Caren L. Freel Meyers Laboratory is to develop novel approaches to kill human pathogens, including bacterial pathogens and malaria parasites, with the ultimate objective of developing potential therapeutic agents. Toward this goal, we are pursuing studies of bacterial isoprenoid biosynthetic enzymes comprising the methylerythritol phosphate (MEP) pathway essential in many human pathogens. Studies focus on understanding mechanism and regulation in the pathway toward the development of selective inhibitors of isoprenoid biosynthesis. Our strategies for creating new anti-infective agents involve interdisciplinary research in the continuum of organic, biological and medicinal chemistry. Molecular biology, protein expression and biochemistry, and synthetic chemistry are key tools for our research.

Work in the Green Lab is centered on the ribosome. The overall fidelity of protein synthesis appears to be limited by the action of the ribosome, which is the two-subunit macromolecular machine responsible for decoding and translating messenger RNAs (mRNAs) into protein in all organisms. Our work is divided into four general project areas. The longest-standing research area concerns the interactions of eubacterial ribosomes and release factors. The goal is to understand the mechanism of action of release factors on the ribosome. A second research area involves biochemical and structure/function studies of the miRNA pathway, particularly the mechanism of action of the Argonaute proteins and their interacting factors. A third area of work in the lab is centered around regulation of eukaryotic translation, specifically in understanding the mechanism behind various mRNA quality control pathways and the interactions of proteins therein, as well as with the ribosome. The newest area of research in the lab extends our strengths in ribosome biochemistry to characterize the translation status of the cell using the ribosome profiling. We are using this technique to better understand the role of several factors involved in eukaryotic and prokaryotic translation fidelity.

The Greider lab uses biochemistry to study telomerase and cellular and organismal consequences of telomere dysfunction. Telomeres protect chromosome ends from being recognized as DNA damage and chromosomal rearrangements. Conventional replication leads to telomere shortening, but telomere length is maintained by the enzyme telomerase. Telomerase is required for cells that undergo many rounds of divisions, especially tumor cells and some stem cells. The lab has 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. The lab also is using the 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 stem cell loss. The lab has 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.

Research in the Brendan J. Canning Lab is focused on mechanistic studies of the cough reflex. Through our work, we identified the afferent nerves that play an essential role in regulating cough. We have also been characterizing the CNS pathways regulating the cough reflex and interactions amongst various afferent nerve subtypes in regulating cough. We have identified key sites of integration of airway afferent nerve input and mechanisms by which afferent nerve subtypes act synergistically to regulate cough. Our experimental approaches include electrophysiological recordings, CNS microinjection techniques, in vivo preparations for monitoring cough and reflex bronchospasm, neuronal tracing and immunohistochemistry.

The Foster Lab uses the tools of protein biochemistry and proteomics to tackle fundamental problems in the fields of cardiac preconditioning and heart failure. Protein networks are perturbed in heart disease in a manner that correlates only weakly with changes in mRNA transcripts. Moreover, proteomic techniques afford the systematic assessment of post-translational modifications that regulate the activity of proteins responsible for every aspect of heart function from electrical excitation to contraction and metabolism. Understanding the status of protein networks in the diseased state is, therefore, key to discovering new therapies. D. Brian Foster, Ph.D., is an assistant professor of medicine in the division of cardiology, and serves as Director of the Laboratory of Cardiovascular Biochemistry at the Johns Hopkins University School of Medicine.

The Caterina lab is focused on dissecting mechanisms underlying acute and chronic pain sensation. We use a wide range of approaches, including mouse genetics, imaging, electrophysiology, behavior, cell culture, biochemistry and neuroanatomy to tease apart the molecular and cellular contributors to pathological pain sensation. A few of the current projects in the lab focus on defining the roles of specific subpopulations of neuronal and non-neuronal cells to pain sensation, defining the role of RNA binding proteins in the development and maintenance of neuropathic pain, and understanding how rare skin diseases known as palmoplantar keratodermas lead to severe pain in the hands and feet.

The Wolfgang Laboratory is interested in understanding the metabolic properties of neurons and glia at a mechanistic level in situ. Some of the most interesting, enigmatic and understudied cells in metabolic biochemistry are those of the nervous system. Defects in these pathways can lead to devastating neurological disease. Conversely, altering the metabolic properties of the nervous system can have surprisingly beneficial effects on the progression of some diseases. However, the mechanisms of these interactions are largely unknown. We use biochemical and molecular genetic techniques to study the molecular mechanisms that the nervous system uses to sense and respond to metabolic cues. We seek to understand the neurometabolic regulation of behavior and physiology in obesity, diabetes and neurological disease. Current areas of study include deconstructing neurometabolic pathways to understand the biochemistry of the nervous system and how these metabolic pathways impact animal behavior and physiology, metabolic heterogeneity and the evolution of metabolic adaptation.

The Fukunaga Lab uses multidisciplinary approaches to understand the cell biology, biogenesis and function of small silencing RNAs from the atomic to the organismal level. The lab studies how small silencing RNAs, including microRNAs (miRNAs), small interfering RNAs (siRNAs) and piwi-interacting RNAs (piRNAs), are produced and how they function. Mutations in the small RNA genes or in the genes involved in the RNA pathways cause many diseases, including cancers. We use a combination of biochemistry, biophysics, fly genetics, cell culture, X-ray crystallography and next-generation sequencing to answer fundamental biological questions and also potentially lead to therapeutic applications to human diseases.

The Shanthini Sockanathan Laboratory uses the developing spinal cord as our major paradigm to define the mechanisms that maintain an undifferentiated progenitor state and the molecular pathways that trigger their differentiation into neurons and glia. The major focus of the lab is the study of a new family of six-transmembrane proteins (6-TM GDEs) that play key roles in regulating neuronal and glial differentiation in the spinal cord. We recently discovered that the 6-TM GDEs release GPI-anchored proteins from the cell surface through cleavage of the GPI-anchor. This discovery identifies 6-TM GDEs as the first vertebrate membrane bound GPI-cleaving enzymes that work at the cell surface to regulate GPI-anchored protein function. Current work in the lab involves defining how the 6-TM GDEs regulate cellular signaling events that control neuronal and glial differentiation and function, with a major focus on how GDE dysfunction relates to the onset and progression of disease. To solve these questions, we use an integrated approach that includes in vivo models, imaging, molecular biology, biochemistry, developmental biology, genetics and behavior.