Elena Casey, see Elena Silva
Development of the neurons in the inner ear
The long-term goal of the research in the Coate laboratory will be to define the signaling mechanisms underlying neural development within sensory systems and how synaptic connections can be reestablished in cases of damage or disease. In the field of developmental neuroscience, we are now at an exciting time where we can take multi-faceted approaches to understanding (with excellent temporal and spatial resolution) the mechanisms by which precise cell types coordinate appropriate axon guidance decisions and synapse formation. In our research, we aim to understand the mechanisms by which spiral ganglion neurons (SGNs) make functional connections with mechanosensory hair cells in the mouse cochlea. We are currently addressing how secreted Semaphorins, which activate Neuropilin/Plexin co-receptors, control SGN axon guidance decisions in the cochlear sensory epithelium. We are also investigating how the transcription factor Pou3f4 controls the expression of axon guidance factors in the developing cochlea (such as ephrins and Eph receptors) and how those factors control cochlear innervation. The cochlea provides an excellent model for discovering how circuits assemble within a complex organ system, as it is composed of an array of cell types and structures precisely arranged to detect a range of sound frequencies.
Cerebral Cortical Development
The Donoghue Laboratory examines the development of the cerebral cortex, the largest and most complex portion of the mammalian forebrain. A battery of molecular, cellular, biochemical, and organismal approaches is used to examine the forces that shape the proper formation of the cortex. For example, current studies focus on how the proliferation of cells in immature cellular zones is controlled in development so that the mature cortex contains the appropriate number of cells. In addition, once cells have stopped dividing, we are interested in the regulatory programs that control their subsequent differentiation in more mature compartments. Together, we are interested in the coordination of cell genesis and cell differentiation in order to produce an integrated neural structure that has the proper cells present in the proper proportions. Mouse models (mutant, transgenic) are used for examining the function of particular genes in vivo and in vitro.
Neural regeneration and neuron-glia interaction
The goal of my research is to understand how glial cells regulate neuronal function in the mammalian central nervous system (CNS). We focus on oligodendrocytes, a type of glia, whose cellular processes engage with and enwrap CNS axons, and form the lipid-rich myelin membranes required for rapid, saltatory axonal conduction. Oligodendrocyte loss or dysfunction has profound impact on brain development, homoeostasis, and aging, and has been implicated in many neurological disorders including certain leukodystrophies, multiple sclerosis (MS), cerebral palsy, Alzheimer’s disease, schizophrenia, and autism.
We are currently investigating the mechanisms by which oligodendrocytes interact and communicate with axons, and how their interactions might promote axonal integrity and survival. We are also investigating the mechanism of CNS regeneration, with a focus on how oligodendrocytes regenerate from endogenous neural progenitor cells to replace myelin during homeostatic turnover or after demyelination. We use primary oligodendrocyte/neuron co-cultures, transgenic mice, and models of experimental CNS injury and demyelination, combined with molecular biology and imaging tools to address these questions.
Neurodegeneration & Neuroinflammation
The Maguire-Zeiss laboratory studies the role of the brain’s innate immune system in neurodegenerative disorders (Parkinson’s disease, HIV-associated neurocognitive disorder). We investigate the signaling responses of glial cells (microglia and astrocytes) to misfolded or pathogen-associated proteins and the subsequent effect on neuronal function. The lab uses a variety of models to address inflammation and neuronal-glial crosstalk, such as cell lines and primary cells derived from animal models, treatment of cells in vitro and in vivo with recombinant and cell-derived proteins, rAAV overexpression of proteins, and transgenic mouse models. We combine these models with biochemical, molecular, and imaging approaches in an effort to identify novel mechanisms of disease. Our hope is that this primary focus on understanding signaling pathways in brain cells will reveal new therapeutic targets for neurodegenerative disorders.
Mode of action of the neuropeptide NAAG
My research group has pioneered study the study of the neuorpeptide NAAG over the past two decades. We pursue the mechanisms through which NAAG chemically communicates information among cells. Our lab identified the receptors that this peptide activates and cloned two enzymes that mediate its inactivation. Currently, we are determining the role of endogenous NAAG at identified synapses, characterizing peptidases that hydrolyze NAAG in the nervous system, and developing novel compounds that inhibit these peptidases. These compounds decrease the rate of inactivation of the peptide and enhance its activity in the nervous system. My research group applies these compounds in animal models of important human disorders including chronic and inflammatory pain perception, schizophrenia, and excitotoxicity associated with traumatic brain injury. Our aim is to develop new therapies for these disorders.
Neural induction in Xenopus leaves
The goal of the Silva lab is to understand the transcriptional regulation of a class of genes involved in the formation of the early vertebrate body plan. Patterning events such as the establishment of neural tissues require a series of signal transduction events that lead to the transcription of a set of genes. Few of the details of transcriptional regulation in vertebrate development have been deciphered. However, the ability to generate transgenic frogs has revolutionized the field, allowing rapid analysis of promoter function in a large number of embryos. This technique, along with embryology, traditional biochemical and molecular assays, and expression screens now enable us to define the factors required for regulation of genes involved in early vertebrate development.