Neurology; Cytoskeleton and cell motility; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Signal Transduction; Inherited Metabolic Disorders; Transgenic organisms
My laboratory seeks to understand the molecular basis of myelination and myelin diseases. Myelin is a multi-lamellar sheath that invests large axons and permits rapid conduction of nerve signals. Failure in myelin synthesis and myelin breakdown cause several important neurological diseases, including multiple sclerosis, leukodystrophies and peripheral dysmyelinating neuropathies. In some of these diseases, genetic mutations cause defects in cytoskeletal, adhesion and signaling molecules. I work with a team of undergraduate and graduate students, postdoctoral fellows, technicians, senior scientists and many international collaborators to discover how these molecules normally coordinate cell-cell and cell-extracellular matrix interactions to generate the cytoarchitecture of myelinated axons. We use a variety of approaches, including generation of mice carrying genetic abnormalities, cultures of myelinating glia and neurons, imaging, biochemistry and morphology to understand the role of these molecules in normal and pathological development. By comparing normal myelination to the abnormalities occurring in human diseases, we aim to identify molecular mechanisms that pharmacological intervention might correct. For example, we described how the protein dystroglycan associates with different proteins, some of which impact human neuropathies, depending on a proteolitic cleavage that can be regulated to improve the disease. Similarly, we found that molecules such as integrins and RhoGTPAses are required for glia to extend large processes that will become myelin around axons. In certain neuromuscular disorders, defective signaling pathways that converge on these molecules cause failure to produce or mantain an healthy myelin Finally, in collaborations with scientists and clinicians in the Hunter J. Kelly Research Institute, we are generating transgenic forms of GalC, an enzyme deficient in Krabbe leukodystrophy, to investigate which cells requires the enzyme. Investigating how GalC is handled may help find a cure for this devastating disease.
Apoptosis and cell death; Inherited Metabolic Disorders; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Regulation of metabolism; Transgenic organisms; Vision science
Our lab is focused on studies of retinal degenerations caused by metabolic defects, particularly dyslipidemias involving defective cholesterol metabolism (e.g., Smith-Lemli-Opitz syndrome), using pharmacological and transgenic animal models. Current studies are focused on the role of lipid and protein oxidation in the underlying mechanisms of photoreceptor cell death in such retinal degenerations, using a combination of genomic, proteomic, and lipidomic approaches.
Bioinformatics; Cell growth, differentiation and development; Genomics and proteomics; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Gene Expression; Stem Cells; Transgenic organisms
My research goal is to gain a better understanding of how proteins that interact with DNA regulate RNA transcription, DNA replication and metazoan development. I mentor undergraduate and graduate students in my lab; we focus on the structure and function of the Nuclear Factor I (NFI) family of site-specific DNA binding proteins, and we are investigating their roles in development. Our work has been made possible by our development of loss-of-function mutations of the NFI genes in the mouse and C. elegans. We are addressing four major questions in my laboratory and in collaboration with a number of talented collaborators: What is the structure of the NFI DNA-binding domain? How does NFI recognize and interact with DNA? Does NFI change the structure of DNA when it binds? What proteins interact with NFI to stimulate RNA transcription and/or DNA replication? These research questions are explored in my lab through two major projects focused on the role of NFIB in lung development and the role of NFIX in brain development. When NFIB is deleted from the germline of mice the animals die at birth because their lungs fail to mature normally. This provides a good model for the problems that occur with premature infants, whose lungs also fail to mature normally. We are using this model to determine how NFIB promotes lung maturation with the goal of being able to stimulate this process in premature infants. In our NFIX knockout animals, the brains of the animals are actually larger than normal and contain large numbers of cells in an area known to be the site of postnatal neurogenesis. We have evidence that NFIX may regulate the proliferation and differentiation of neural stem cells, which produce new neurons throughout adult life. Our aim is to understand the specific target genes that NFIX regulates in the adult brain to control this process of neurogenesis.
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Genomics and proteomics; Molecular genetics; Stem Cells; Transcription and Translation; Transgenic organisms; Vision science
My lab is interested in how global gene expression advances from one state to the next in time and space during development to promote the specification and differentiation of individual retinal cell types from multi-potent neural progenitor cells. We focus on the gene regulatory network (GRN) involved in the formation of one retinal cell type, retinal ganglion cells (RGCs). RGCs are the only projection neurons in the retina and connect the retina to the brain through the optic nerve. Death of RGCs is cause of vision loss in glaucoma and other retinal diseases. Several key transcription factors (TFs) functioning at different stages of RGC development have been identified; Math5 is essential for RGC fate specification, whereas Pou4f2 and Isl1 are required for their differentiation. Our previous study has established a tentative model for the RGC GRN, in which these TFs occupy key node positions. Current projects in the lab are aimed at further understanding how these transcription factors specifically regulate their target genes and how they interact with each other. Considerable efforts are also placed on identifying novel key regulators in the GRN. Our studies employ a combined approach of genetics, genomics and bioinformatics. Our eventual goal is to use the knowledge learned from our studies to develop new therapies for various retinal diseases.
Inherited Metabolic Disorders; Membrane Transport (Ion Transport); Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; Transgenic organisms; Vision science
Most physiological processes and numerous disease states influence or are influenced by pH. Even relatively small deviations in whole body pH can have devastating consequences for our health. Our bodies are subject to a constant challenge from dietary and metabolic acids, thus it is critical for the body to have mechanisms that tightly regulate pH. Blood plasma pH is maintained at a value close to 7.4, predominantly thanks to the buffering action of 24 mM bicarbonate (HCO3-). HCO3- neutralizes acid, generating carbon dioxide and water (HCO3- + H+ to CO2 + H2O), preventing lethal acidosis. I study the SLC4 family of membrane proteins that move HCO3- across cell membranes. Notable members include  the Na/2HCO3 cotransporter NBCe1-A that reclaims HCO3- from filtered blood plasma in kidney tubules (preventing loss of vital plasma HCO3- to the urine),  NBCe1-B that promotes fluid removal from the corneal stroma (preventing corneal edema and vision loss),  the Cl-HCO3 exchanger AE1 that promotes O2-CO2 exchange in red blood cells, and  SLC4A11 that conducts H+ and promotes corneal clarity. Dysfunction of SLC4 family members is associated with renal tubular acidosis, blindness, cancer, deafness, epilepsy, and hypertension.
Behavioral pharmacology; Cardiac pharmacology; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular Basis of Disease; Neurobiology; Neuropharmacology; Signal Transduction; Transgenic organisms
With over 400 genes coding for them in humans, ion channels play a significant role in most physiological functions. Drug-induced channel dysfunction often leads to a variety of disorders and results in significant incidence of serious injury and death. We investigate molecular mechanisms underlying neurodegenerative disorders and cardiac arrhythmias induced by ion channel dysfunction arising from genetic factors and/or drug interactions. The tools used for these investigations include genetic, electrophysiologic, pharmacologic, molecular and cell culturing methods. Preparations used for experiments include Drosophila as a genetic model system, and human cell lines expressing human ion channels that play an important role in critical-to-life functions including cardiac rhythm, respiration and the central nervous system.