Program Faculty

Dr. Howard Federoff is Professor of Neurology, Medicine, Microbiology & Immunology, Director of the Center for Aging and Developmental Biology and Senior Associate Dean for Basic Research. His research aims at elucidating the molecular mechanisms that underlie development and plasticity in the nervous system and exploiting these to modify the intact damaged nervous system. His laboratory has developed several lines of investigation, including (1) development of herpes virus vectors to direct long-term expression of therapeutic genes to different cellular compartments within the intact developing and adult CNS, (2) elucidating the role of NGF in the hippocampus using a binary germline-somatic transgene system based on loxP/cre recombinase to produce postnatal genetic mosaicism for NGF gain of function along the NGF-responsive septohippocampal pathway, and (3) development of somatic mosaic mice to examine the synergy between environmental neurotoxicants and specific neuronal vulnerability genes as a model for Parkinson"s disease. These research projects all involve molecular, anatomic and behavioral assays to assess changes in the function.

Dr. Robert Freeman is Associate Professor of Pharmacology and Physiology. His research investigates the molecular mechanisms that underlie programmed cell death in the developing and adult nervous system. In the developing nervous system, programmed cell death is important for the proper formation of connections between neurons and target cells. In contrast, when cell death occurs inappropriately, it may contribute to a wide variety of pathological conditions including neurodegenerative disease, neurotoxicity, and stroke.

As a model system, Dr. Freeman studies the death of neurons that are deprived of survival-promoting molecules such as nerve growth factor (NGF). Because the death of these neurons requires ongoing RNA and protein synthesis, genes specifically expressed during programmed cell death are likely to be important components of the cell death program. Consistent with this hypothesis, several genes have been identified that increase in expression in neurons deprived of NGF. One of these genes, SM-20, induces caspase-dependent neuronal death when expressed in neurons. The SM-20 protein appears to be a novel mitochondrial protein and efforts are underway to characterize its biochemical function. Ultimately, the goal is to determine how SM-20 and other proteins activated during the pre-commitment stages of neuronal death function, and how, in turn, they activate downstream events in the cell death program. the developmental, cellular and molecular biology of oligodendrocytes.

Dr. Robert Frisina, Professor of Otolaryngology, Surgery, and Neurobiology and Anatomy, investigates the processing of complex sounds such as speech, and how this processing changes during aging and development. A multidisciplinary and multifaceted approach is undertaken. Neurophysiological investigations focus on sound processing in the ear and brain at the level of the single neuron employing multi-barrel microelectrodes with both recording and iontophoresis capabilities. Neuroanatomical and immunocytochemical investigations aim at imaging and revealing the regions of the brain and neural pathways related to hearing. Parallel human perceptual, behavioral and electrophysiological studies are also conducted in collaboration with other departments and the National Technical Institute for the Deaf (NTID). Dr. Frisina also conducts developmental clinical studies in collaboration with the Center for Oral Biology, Pediatrics Department, the Eastman Dental Center, NTID and the Rochester School for the Deaf. This clinical research effort is aimed at furthering an interdisciplinary understanding, including genetic bases, of the relations between craniofacial dysmorphologies, such as cleft lip/palate, and communication disorders such as hearing loss and deafness. A pilot program is ongoing to investigate the relationship between auditory temporal processing abilities and reading/language problems in elementary students.

Dr. Lin Gan is Assistant Professor of Neurobiology and Anatomy in the Center for Aging and Developmental Biology. His research program aims at elucidating the fundamental mechanisms regulating the normal development and maintenance of these neurons at the molecular level. The focus is on identifying genes required for neuron differentiation and survival, investigating the genetic pathways involved in these processes, and developing therapies for blindness and deafness via gene therapy and stem cell replacement. Dr. Gan"s laboratory is currently investigating the roles of two classes of transcription factors in the development and survival of mouse retina and inner ear: (a) Math5 and Math1, the basic helix-loop-helix (bHLH) transcription factors homologous to Atonal, a Drosophila proneural transcription factor, and (b) Brn-3 factors, the Class IV POU-domain transcription factors. Using homologous recombination in murine embryonic stem (ES) cells to mutate math5 and brn-3 genes, his laboratory has shown that the math-class genes regulate the differentiation of neuronal progenitor cells into specific types of neurons and that brn-3 genes are required for the maturation and survival of post-differentiation neurons.

Dr. Roman Giger is Assistant Professor of Neurology in the Center for Aging and Developmental Biology. His research is in the areas of nervous system development and neuronal regeneration following traumatic injury. In particular, he is interested in the molecular mechanisms underlying axonal growth and pathfinding in the developing and regenerating nervous system. The main goal of his research is to gain insight into how repulsive axon guidance molecules function. The identification of families of axon guidance molecules and their cognate receptors, coupled with powerful genetic intervention in the mouse, opens exciting new avenues for studying mammalian nervous system development and regeneration in vivo. Dr. Giger"s long-term research goals are (1) to elucidate the mechanisms and molecules by which axons are guided to their targets during neuronal development and (2) to apply this knowledge to systems that model traumatic injury to the adult nervous system in order to develop means to promote neuronal regeneration.

Dr. Rulang Jiang is Assistant Professor of Biology in the Center for Oral Biology. His research focuses on investigating the genetic and molecular mechanisms underlying craniofacial and neural development. A major project is to study the roles of the Notch signaling pathway in craniofacial and neural development. His laboratory has generated a targeted mutation in the mouse Jag2 gene, which encodes a cell surface ligand for the Notch family of receptors, and showed that Jag2 mutant mice exhibit cleft palate, syndactyly, and defects in inner ear development, phenotypes that resemble several human birth defects. The developmental defects in Jag2 mutant mice correlate with Jag2 gene expression in the orofacial epithelium, the apical ectodermal ridge of the limb bud, and the inner ear epithelium during embryogenesis. Ongoing work is analyzing compound mutant mice carrying mutations in Jag2 and either Dll1 or Dll3 for synergistic effects of these mutations on neural development. His laboratory has also characterized the expression patterns of the Notch receptors during craniofacial and neural development and identified Notch1 as the most likely endogenous receptor for Jag2 in the craniofacial tissues and the neural tube. Hyper- and hypomorphic point mutations in the Notch1 gene using Cre/loxP-mediated gene targeting are being generated to analyze the function of the Notch1 gene in craniofacial and neural development. Other genetic pathways in craniofacial and neural development are also being investigated, as mutant genes are positionally cloned and the resultant developmental defects in the mutants are characterized.

Dr. David Kornack, Assistant Professor of Neurobiology and Anatomy in the Center for Aging and Developmental Biology, studies neurogenesis in the mammalian brain, particualrly in the cerebral cortex. Since brain size and function depend on the generation of the appropriate number of neurons during development and their proper assembly into neural circuits, he is investigating how neurogenesis is controlled during development and why it persists in only a few particular brain regions in adulthood. Molecular, cellular and anatomical techniques are being applied to a variety of mammalian models to address these issues. The mechanisms that govern neurogenesis underlie the developmental basis of both the generation of neural diversity across species as well as the pathogenesis of abnormalities in humans. Moreover, continued neuronal production may have implications for plasticity in the adult brain - particularly for enhancing the brain"s own capacity for self-repair after neuronal loss due to injury or neurodegenerative disease.

Dr. Mark Noble, Professor of Genetics in the Center for Cancer Biology, utilizes stem cell technology to understand neuronal development, mechanisms of injury and regeneration. His research bridges developmental neurobiology and cancer biology by investigating the general principles underlying precursor cell function. In addition, his studies are also revealing that a number of the chemical agents used to treat cancer are toxic to many normal brain cell populations, thus accounting for the cognitive impairment that increasingly is being recognized as a potential side effect of cancer therapy. His laboratory is conducting a comparative analysis of stem cells, lineage-restricted precursor cells and differentiated cells of the normal brain with brain tumor cells, with the goal of developing means of selectively protecting normal cells. An important component of this research direction is investigating the potential for multiple growth factors to modulate the balance between self-renewing division and differentiation of stem cells, lineage-restricted precursor cells. These studies have thus far revealed a complex and sophisticated interplay between cell-intrinsic regulatory mechanisms and the response of a precursor cell to environmental signals and ongoing work is directed towards both increasing our understanding of this interplay at the molecular and cellular levels and exploiting such understanding to enhance tissue repair.

Dr. Kathy Nordeen, Professor of Brain and Cognitive Sciences, investigates the biological mechanisms that enable learning and memory. Her laboratory exploits the fact that many behaviors are best learned during discrete developmental periods. Such "sensitive" periods reflect a powerful influence of experience on neural and behavioral development, and are characteristic of imprinting, the development of normal sensory function, and human language acquisition. To identify cellular mechanisms that mediate plasticity during sensitive periods, she studies vocal learning in songbirds. Avian song learning involves memorization of song material followed by vocal practice that is guided by auditory feedback and most species can learn to sing only during restricted developmental or seasonal periods. Behavioral, anatomical, pharmacological, and molecular analyses are employed in combination to determine how maturational changes in neural organization and function influence, or are influenced by, vocal learning. The goal is to determine how information is stored through experience-dependent modifications of the developing nervous system .

Dr. Ernest Nordeen is Professor of Brain and Cognitive Sciences and Associate Professor of Neurobiology and Anatomy. His laboratory is interested in identifying cellular processes and molecules that mediate the influence of gonadal hormones (e.g. androgens and estrogens) on the development and modifiability of neural circuits controlling learned behavior. His research focuses on a sexually dimorphic system controlling the learning and production of male courtship song in birds. One way hormones affect the development of this behavior is by controlling the pace of vocal development and thereby regulating sensitive periods for vocal learning. Ongoing experiments are investigating how hormones influence the developmental regulation of molecules fostering synaptic plasticity and learning (e.g. NMDA receptors and/or neurotrophins). The overall goals are twofold: to use gonadal hormones as tools to manipulate and understand basic cellular processes that orchestrate neural development and to elucidate how hormones influence the complex cognitive processes underlying perception, learning and memory.

Dr. Lisa Opanashuk, Assistant Professor of Environmental Medicine, is investigating the impact of perinatal exposure to environmental agents on neurogenesis and neuronal differentiation in the developing brain. Both in vivo and in vitro models are being used to identify cellular targets and molecular mechanisms for neurotoxicity. Her laboratory uses morphological and biochemical techniques to define toxicant effects on cell proliferation, neuronal migration, neurite development, synaptogenesis and apoptosis. She is also interested in correlating morphologic changes following toxicant exposure with alterations in expression of genes and proteins related to cytoskeletal dynamics, cell cycle control, and neurotrophic factor signaling. Ongoing projects in her laboratory involve testing of several agents: endocrine disruptors, such as polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); abused substances (toluene and nicotine); and metals (mercury). The long-term goal of Dr. Opanashuk"s research is to determine the relationship between disrupted neuronal production or maturation and functional deficits produced by toxicant exposure during critical periods of brain development.

Dr. David Pearce, Assistant Professor of Biochemistry and Biophysics in the Center for Aging and Developmental Biology, studies protein turnover, particularly the degradation of mitochondrial proteins in the yeast Saccharomyces cerevisiae. This interest in mitochondrial protein turnover has lead to research focusing on the childhood disease, Batten disease. There is an apparent defective turnover of mitochondrial ATPase subunit c in individuals with Batten disease, which has lead to use yeast as a model to study this disease. Batten disease is one of the more common childhood neurodegenerative diseases. Children with this disease usually suffer visual failure, psychomotor deterioration, seizures and premature death. Although the underlying defect to this disease, a defective CLN3 gene, was first identified in 1995, very little progress has been made in understanding Cln3p function and how a defective Cln3p causes Batten disease. Individuals with Batten disease exhibit accumulation of lipopigments in the lysosome, predominantly the proteolipid, mitochondrial ATPase subunit c, leading to the belief that the turnover of this protein is somehow affected. Dr. Pearce"s laboratory has cloned the yeast homolog to Cln3p, designated Btn1p, and has established that this protein is not involved in the degradation of mitochondrial proteins. He has established that vaculolar/lysosomal pH regulation is altered in yeast lacking Btn1p, and is using the numerous genetic techniques available to a yeast molecular biologist to study the function of Btn1p, which can then be applied to understanding Batten disease.

Dr. Douglas Portman is Assistant Professor of Biomedical Genetics in the Center for Aging and Developmental Biology. His research concerns the genetic mechanisms that control neural development and function in the nematode C. elegans. Taking genetic, genomic and biochemical approaches, his current work focuses on the development of sensory organs called rays in C. elegans males and their roles in mediating behavior. Each ray comprises three cells that arise clonally from a single precursor, making ray development an ideal model to dissect the regulatory mechanisms that control neurogenesis and the establishment of neuronal subtype. The C. elegans atonal/MATH ortholog lin-32 (a bHLH transcription factor) acts in a proneural capacity to specify the neural competence of ray precursors, but also has separate functions required to allow the differentiation of each of the three ray cell types. Genetic and genomic experiments currently in progress have identified several transcriptional regulators that may function in parallel with or downstream of lin-32 to specify individual ray cell fates. These studies have also identified a set of five co-regulated, novel genes expressed in the ray neurons that appear to be important for mediating mechanosensory behavior. Current experiments are aimed at understanding how multiple regulatory inputs converge on these genes to restrict their expression to a specific neuronal subtype.

Dr. Peter Shrager, Professor of Neurobiology and Anatomy, studies the cellular and molecular mechanisms involved in the process of ion channel and receptor clustering. A variety of cellular models are being employed. One such model is the neuromuscular junction, where the dynamics of axon-glia interaction are investigated to understand targeting of sodium and potassium channels to specific microcompartments at the node of Ranvier. In another model, selective sodium channel clustering within the initial segment of the axon is examined in a primary culture system consisting of developing neurons. A combination of molecular manipulations and immunocytochemistry with electrophysiology are employed to investigate both localization and function, as well as the mechanisms behind this early polarization of the neuron.

Dr. Michael Weliky, Assistant Professor of Brain and Cognitive Sciences and Center for Visual Science, conducts vision research focused on two primary areas. The first area is the investigation of activity-dependent mechanisms of visual cortical development. These studies utilize a variety of experimental approaches. One approach involves multi-electrode recording methods to study the correlational structure of spontaneous activity within the developing brain in vivo and how this may prefigure adult visual system architecture such as cortical orientation/ocular dominance columns and neuronal receptive field structure. A second approach to studying the role of neuronal activity in brain development is utilizing direct electrical stimulation of the optic nerve and cortex to disrupt normal patterns of neuronal firing by introducing new and controllable correlation patterns. Finally, pharmacological and viral gene transfer techniques are being utilized to manipulate endogenous levels of a variety of molecules within the visual pathway such as neurotrophins and its effect upon cortical development is being assessed. Dr. Weliky"s second area of research is in neural mechanisms of visual perception and cognition. This work is utilizing multi-electrode recording arrays to record patterns of neuronal activity across single and multiple visual cortical areas. Computational methods are being used to analyze how complex visual stimuli, such as natural scenes, are represented and encoded by neuronal population activity.

Dr. Hermes Yeh is Professor of Pharmacology and Physiology in the Center for Aging and Developmental Biology. He has had a long-standing interest in neurotransmitter interactions in the developing central nervous system, and has employed a variety of electrophysiological techniques, ranging from extracellular single-unit recording in vivo to patch clamp recording in vitro to investigate the cellular and subcellular bases of interaction and modulation of neurotransmitter receptors. He is one of the pioneers in developing and employing the technique of combined patch clamp recording and single-cell gene profiling to correlate neurotransmitter function and subunit gene expression in the same neuron. Using this approach, a major research effort in his laboratory has been to correlate changes in GABAA and glutamate receptor function with the dynamic switches in subunit gene expression in neuronal development as well as following chronic exposure to neuroactive drugs of abuse, such as alcohol. The combined investigation of receptor function and gene expression is being extended to include the detection of candidate receptor subunit proteins in the same neurons. Recent developments in his research programs include a projects that investigates (1) the effects of neurotrophins on the growth and neuroreceptor expression in cerebellar neurons, (2) the regulation of tangential migration of GABAergic interneurons during corticogenesis by developmental neurotransmitters, and (3) NGF-induced synaptic and functional plasticity within the septohippocampal system.