1997 — 1999 |
Corfas, Gabriel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Basis of Neuron/Gila Interactions in the Cns @ Children's Hospital Boston
Neuron-glia interactions play a critical role during the formation of the central nervous system. Glial cells provide the pathway for the migration of postmitotic neurons away from the germinal layers. Neurons influence the proliferation, survival and differentiation of glial cells. A variety of studies have demonstrated that glia and neuronal-derived factors play critical roles in neuronal and glia precursor proliferation and differentiation, but information abut the nature of these signals remains scarce. The long range objective of the proposed research is to understand the molecular mechanisms controlling neuron-glia interactions in the developing mammalian brain. We are studying a new family of growth factors, the neuregulins, which appears to be implicated in mediating neuron- glia interactions in the peripheral and central nervous system. We now have evidence suggesting that neuregulins may play a role in neuron-glia interactions in the developing cerebellum. We have shown that neuregulin receptors, erbB4, is expressed in the radial glial fibers over which these neurons migrate. The expression of these molecules is developmentally regulated, and restricted to the period of granule cell migration. We have also demonstrated that 1) cerebellar astroglia in culture express erbB4, 2) glial erbB4 expression is regulated by extracellular signals, and 3) glial cells response to neuregulin stimulation in the same manner they respond to contact with neurons. These observations suggest that neuregulin may mediate interactions between granule cells and Bergmann glia, and that these interactions may be important for granule cell migration. The work proposed here is directed to elucidate the regulation and functions of neuregulines in the developing central nervous system. The specific aims of the proposed research are: 1) To identify signals cells that regulate the expression of erbB receptors in cerebellar astroglial cells; 2) To determine effects of NRG on Bergmann glial cell biology, and to determine the contribution of NRG to the effects of granule neurons on the glial cells; 3) To determine the role of NRG in granule cell migration. We will study the role of neuregulin in cerebellar granule cell - Bergamann glia interactions in vitro using cellular and molecular techniques. Neuregulin receptors have a wide range of normal biological actions, but are also proto-oncogenes. Therefore, it is likely that alteractions in the function or expression of either ligand or receptors, will be involved in developmental processes that lead to cancer, mental retardation, epilepsy and other central and peripheral nervous system diseases.
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0.976 |
2000 — 2007 |
Corfas, Gabriel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Basis of Neuron-Glia Interactions in the Cns @ Children's Hospital Boston
DESCRIPTION (Applicant's abstract reproduced verbatim): Neuronal migration, the process by which neurons move from the germinal layers of the brain to their final destination in the cortex, is a critical step in the formation of the brain. Failure in this migration has been implicated in several disease states including epilepsy, mental retardation and schizophrenia. The long-term goal of this research is to understand the molecular and cellular mechanisms that induce and regulate neuronal migration. Neurons migrate in close association with glial cells, either radial glia or glial tubes, which provide a scaffold for neuronal movement. This application aims to further characterize the nature of the signals that induce 1) the formation of the glia scaffolds and 2) the migration of neurons along these glia. We have identified two molecules that mediate critical interactions between migrating neurons and their associated glia. We have shown that the growth factor neuregulin (NRG) is produced by neurons and activates erbB4 receptors in glia, leading to the formation of radial glia, which then in turn support the migration of neurons. We have recently found that glial cells secrete a soluble protein, which we have called MIA (Migration Inducing Activity) that induces the migration of neurons. Thus, NRG and MIA appear to be critical in the neuronglia interactions responsible for neuronal migration. The present application extends these observations to investigate the signaling mechanism by which these molecules induce neuronal migration. Specific Aim 1 will use mutagenesis and phospho-peptide mapping to study erbB4 receptor signaling mechanisms, and test the hypothesis that the effects of this receptor tyrosine kinase are dependent upon specific features of erbB4. Specific aim 2 will purify and clone the MIA protein, characterize its biological properties and test the hypothesis that the expression of MIA is regulated by NRG and erbB4 signaling.
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0.976 |
2001 — 2002 |
Corfas, Gabriel |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Core--Cellular Neuroscience Facility @ Children's Hospital Boston
DESCRIPTION: The Cellular Neuroscience Core was formed from the previous Histology and Electron Microscopy Cores. The Histology Core originated under the leadership of Dr. Richard Sidman, with support from the Chief Technologist, Mr. Pieter Dikkes. The Electron Microscopy Core was initiated under the leadership of Dr. Hannah Kinney, who was the first Director of the combined Cellular Neuroscience core. The current director, Dr. Gabriel Corfas, has de-emphasized the electron microscopy aspect of the service in favor of providing more extensive, high throughput services that better meet the current needs of the 37 investigators routinely using this Core. These methods of tissue preparation for structural and molecular anatomical examination include preparation of tissues for standard histology, electron microscopy, confocal microscopy, in situ hybridization, and immunocytochemistry. In addition, this Core provides perfusion of rodents for tissue examination. An emphasis of the Core is to train Center investigators and their associates in methods of tissue preparation. The Cellular Neuroscience Core also provides morphological and neuropathological consultation to investigators. Staff includes the Chief Technologist with 35 years of experience, and a to-be-named technologist with less experience.
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0.976 |
2002 — 2013 |
Corfas, Gabriel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Trophic Interactions in Developing and Adult Inner Ear
DESCRIPTION (provided by applicant): The cellular and molecular mechanisms underlying long-term neuronal survival in the inner ear remain poorly understood. Histopathological correlations have suggested that hair cells are a critical source of survival signals for the VIIIth nerve. However, our work indicates that supporting cells in both cochlear and vestibular epithelia play key roles in neuronal maintenance via the neuregulin 1-erbB receptor and neurotrophin-Trk signaling pathways. Postnatal loss of erbB signaling in supporting cells leads to neuronal degeneration, preceded by a specific loss of NT3 in the cochlea and BDNF in the vestibular organs, at a time when these neurotrophins (NTs) are expressed primarily by supporting cells. Since erbB receptor signaling induces NT expression in other non-neuronal cells, and since inner ear sensory neurons express NRG1, we hypothesize that: NRG1, produced by cochlear and vestibular sensory neurons, induces supporting cells to express NTs, NT3 in the organ of Corti and BDNF in the vestibular epithelia. These NTs, acting back on the neurons, maintain their synaptic contacts with hair cells, induce their survival and preserve their function. We will test this hypothesis using genetically modified mice. In Aim 1, inducible cell-specific knockouts will test if elimination of either NT3 or BDNF in supporting cells or hair cells causes neuronal degeneration and inner ear dysfunction; and conditional cell-specific overexpression transgenics will test if the neuronal degeneration caused by loss of erbB signaling in supporting cells can be rescued by increasing NT expression. In Aim 2, we evaluate inner hair cell contributions to long-term neuronal maintenance using mice lacking the high-affinity thiamine transporter such that dietary thiamine restriction leads to widespread and selective loss of inner hair cells, without damage to supporting cells. Inner ear tissues will be quantitatively assessed over time by confocal morphometry of hair cell synapses and sensory ganglion cells, functional tests of evoked responses, and assessment of gene levels/patterns of expression of key trophic factors and their receptors using RT-PCR and in situ hybridization. Comparison of phenotypes obtained when controlling the up- or down-regulation of NT3 vs. BDNF in hair cells vs. supporting cells at different post-natal ages will provide insights into the specific roles of each neurotrophin, the cells involved in the signaling pathways, and the age-dependence of neuronal susceptibility to trophic factor deprivation. These experiments will provide important insights into the pathogenesis and potential treatment of sensorineural hearing loss and peripheral balance disorders. Progressive dysfunction of the inner ear is an important health issue. In spite of the high incidence of hearing and balance disorders, the cellular and molecular mechanisms that contribute to the long-term integrity of inner ear structure and function remain poorly understood. This project will investigate the cellular and molecular mechanisms involved in the long-term survival and function of inner ear sensory neurons using transgenic mouse models.
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1 |
2008 — 2010 |
Corfas, Gabriel |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Cellular Neuroscience Core @ Children's Hospital Corporation
3.a.2. Overall Objective The overall objective of the Cellular Neuroscience Core is to provide Center investigators access to high quality methods of tissue preparation for state-of-the-art structural and molecular anatomical examination in research projects relevant to the mission of the MRDDRC. Tissues are prepared for standard histology, electron microscopy, confocal microscopy, in situ hybridization, and immunocytochemistry. The Cellular Neuroscience Core also provides for the perfusion of rodents for the purpose of tissue examination and for the design, production and validation of antibodies for immunostaining. A major emphasis of the Core is to provide training for Center investigators and their trainees in the various methods of tissue preparation in order to facilitate the advancement of MRDDRC research. Central to the studies of the normal and abnormal development of the nervous system in humans, as well as in animals, is knowledge of the morphological and topographical features of brain development. For this purpose, the Cellular Neuroscience Core also provides skilled neuropathologists and neuroscientists for consultation. In addition, the Cellular Neuroscience Core provides advice on the use of new online gene expression databases such as Gensat, Functional Genomic Atlas of the Mouse Brain and others. The information available in these databases can, in some instances, help in experimental design and selection of genes of interest for MRDDRC investigators. Finally, because the Core personnel have a wealth of information about the ongoing histology-based projects in the MRDDRC laboratories, the Core fosters collaborations between MRDDRC investigators by linking groups with common interests and complementary expertise and/or tools.
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0.976 |
2008 — 2009 |
Corfas, Gabriel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Basis of Neuron-Gila Interactions in the Cns @ Children's Hospital Corporation
Oligodendrocytes (OLs) and the myelin they form are essential for normal brain function. Loss or dysfunction of these cells has been implicated in several diseases, from multiple sclerosis to psychiatric disorders such as schizophrenia and depression. Therefore, understanding the mechanisms that regulate OL and myelin development should provide insights into the pathogenesis of these diseases and possibly to the development of new therapeutic approaches. It has been proposed that the trophic factor neuregulin 1 (NRG1) and its receptors, the erbB receptor tyrosine kinases, regulate important aspects of OL development. OLs and their precursors (OPCs) express erbB receptors. NRG, which is produced by neurons, activates erbB receptors in OPCs and mature OLs in culture and has effects on their state of differentiation and proliferation in vitro. However, the roles of NRG1- erbB signaling in OL development and the mechanisms by which this occurs remain poorly understood. Recent studies suggest that the biological outcome of NRG1-erbB signaling in OPCs may depend on which NRG1 isoform is involved and which erbB receptor(s) is activated. We propose to test this possiblity using genetically modified mice and cells in tissue culture. The specific aims of this proposal are 1) to determine the roles of erbB signaling in OL development and myelination in vivo after birth. This will be achieved by analyzing the phenotypes of mice in which the function of all NRG1 receptors (erbB2, erbB3 and erbB4) is eliminated in cells of the OL lineage by expression of a dominant-negative erbB receptor, and mice in which OL expression of either erbB2 or erbB4 is eliminated by cell specific Cre/loxP recombination system, and 2) to determine the mechanisms by which NRG1-erbB signaling regulates OL development. We propose to study the effects of different NRG1 isoforms on OPC proliferation, survival, differentiation and gene expression. The experiments will also test if the manner in which the different NRG1 molecules are presented, either in cell-cell contact or as soluble factors, influences their bioactivities. The effects of activation of the different erbB receptors in OPCs will be tested by examining what happens to OPCs when the receptors are removed one at a time, or when different erbB receptor homo- and heterodimers are activated. We will also test the hypothesis that erbB4 regulates OPC development through a novel presenilin-dependent nuclear signaling pathway we have recently discovered.
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0.976 |
2009 — 2010 |
Ceriani, Maria Fernanda Corfas, Gabriel Schinder, Alejandro Fabian (co-PI) [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Mechanisms of Progressive Neurodegeneration: Combining Forward Genetic Screens In @ Fundacion Instituto Leloir
DESCRIPTION (provided by applicant): Age is the major risk factor for neurodegenerative diseases. As society age's neurodegeneration become increasingly common, yet the molecular and cellular mechanisms underlying this complex condition remain largely unknown. The goal of this proposal is to explore novel avenues to investigate mechanisms of neurodegeneration in an unbiased manner. A misexpression screen that takes advantage of the power of Drosophila genetics is used to identify genes that may be involved in late-onset behavioral defects (aging). Novel genes that are thus identified to be involved in late neuronal dysfunction can be then characterized and validated in the Drosophila central nervous system by combining genetics, imaging and behavior. Effects of altered gene function can also be tested and validated in the mouse brain, by retrovirus-mediated expression in neurons of the young adult and aging brain. Cell-autonomous effects emerging from these studies will largely contribute to understanding the specific aspects of neuronal function that are affected by the candidate gene. In parallel, a transgenic mouse model will be built based upon the gene identified in Drosophila. Altered gene function in the mouse brain will serve as a tool to characterize the effects on neuronal networks and, ultimately, on brain function, from simple locomotor behaviors to complex learning traits. In addition, transgenic mice should in the future be amenable to high throughput chemical/ small molecule library screens to identify drugs interfering with the degenerative process. A particular gene that emerged from the fly screen, enabled, has been selected as a proof of principle for the approach. The success of the proposed project relies on building a close interaction among two laboratories at the Leloir Institute (Buenos Aires) and a laboratory at Childrens Hospital, Harvard Medical School. Graduate students, postdoctoral fellows and young investigators will have the opportunity to obtain training at Harvard to generate, characterize and maintain transgenic mice. This know-how will certainly improve the capabilities to develop novel models of neurodegeneration at the foreign institution. The ultimate goal is to establish a long-term collaboration in order to bring our local scientific community in closer contact with novel technologies for research on this challenging topic. To accomplish such goal the preparation of full RO1 research proposal is warranted.
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0.901 |
2015 — 2019 |
Corfas, Gabriel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Trophic Interactions in the Developing and Adult Inner Ear
DESCRIPTION (provided by applicant): Recent studies of noise-induced and age-related hearing loss show that loss of synapses between cochlear nerve terminals and inner hair cells (IHCs), rather than hair cell damage, is often the first degenerative event. Noise exposures causing only temporary threshold shifts, and no loss of hair cells, nevertheless cause rapid and permanent loss of IHC synapses, followed slowly by death of spiral ganglion neurons (SGNs). A similar view of the importance of synaptopathy has emerged with respect to the aging ear. Even without purposeful noise exposure, loss of IHC synapses in mice progresses steadily throughout life, long before the loss of hair cells and SGNs, and similar findings are emerging from post-mortem studies of human ears. Thus, understanding the mechanisms that underlie the formation, maintenance, and regeneration of the IHC-SGN synapse are key to understanding the cellular and molecular basis of acquired hearing loss and thus in the development of rational therapies. Using cell-specific, inducible gene recombination in several novel mouse transgenic lines, we showed that neurotrophin 3 (NT-3) derived from cochlear supporting cells is a key regulator of IHC synapse formation and maintenance in the neonate, and that neonatal NT-3 overexpression in supporting cells enhances synaptic and functional recovery after acoustic overexposure in the adult. Here we will test the hypotheses that 1) NT-3 is critical for regulation of IHC synapses in the adult, and 2) that age- related or noise-induced cochlear neuropathy can be modulated by up- or down-regulating NT-3. Aim 1 will determine the roles of NT-3 in regulating IHC synapses in the adult and aging ear by genetically inducing supporting-cell NT-3 overexpression or deletion in the adult cochlea and assessing the effects on cochlear structure and function over short (wks) and long (months) survival. Aim 2 will test the hypothesis that increases or decreases in cochlear NT-3 can influence the severity of, or recovery from, noise-induced cochlear neuropathy using genetic and pharmacological approaches. We will over- or under-express NT-3 in supporting cells by genetic means either 1 wk before or 1 day after a neuropathic noise exposure and monitor cochlear function via ABRs and DPOAEs at different intervals, out to 6 months. For the pharmacological approach, NT-3 will be delivered via round window application in a slow-release gel. For both aims, we will monitor changes in cochlear function via ABRs and DPOAEs, and cochleas will be collected either for RT-PCR analysis of NT-3 expression and/or for histological analysis of hair cell and SGN counts as well as IHC synapse number and morphology.
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1 |
2017 — 2021 |
Corfas, Gabriel |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Advanced Research Training in Otolaryngology @ University of Michigan At Ann Arbor
ABSTRACT Physician-scientists and academic physicians play key roles in discoveries and the ensuing translation of research advances into improved health care for patients, a process central to the NIH Roadmap. Therefore, dedicated and intensive research training is essential to developing the next generation of clinician-scientists. Otolaryngologists are most likely to undertake research in the NIDCD mission areas of hearing, balance, voice, communication disorders, taste, smell, and related cellular biology. The goal of this competitive renewal is to continue to provide research experiences at different stages of medical training, involving medical students, resident physicians, and post-residency fellows. Specifically, we propose to support: 1) 12-month predoctoral research experience for two medical students interested in otolaryngology and the communication sciences, to encourage pursuit of residencies that include research training and, ultimately, academic careers; 2) 18 months of postdoctoral research training for one otolaryngology resident per year, to define and develop a research interest to be continued as an academic faculty member; and 3) 12-month postdoctoral post- residency fellowship for one trainee per year to complement their clinical subspecialty training and prepare for academic careers as clinician-scientists. Preceptors have been selected from the internationally-recognized faculty at the University of Michigan, consisting of basic science, translational and clinical researchers with primary appointments in the departments of Otolaryngology-Head & Neck Surgery, Neurology, Psychiatry, Family Medicine, Human Genetics, Biomedical Engineering and Biologic & Materials Sciences. Major focuses of research include the mechanisms of hearing loss and hearing restoration, head and neck oncology, tissue bioengineering, nerve regeneration, 3D printing, applied cochlear implant research and health services for deaf and hard of hearing patients. Each trainee will have academic otolaryngology faculty as either a primary or a secondary mentor. Emphasis will be placed on project design/translational potential, multidisciplinary collaboration, grantsmanship, manuscript development, and presentation of research proposals and findings. Opportunities will be provided to attend extramural or intramural conferences or educational courses relevant to the trainee's chosen research discipline. The research programs and facilities of the Department of Otolaryngology-Head and Neck Surgery and the Kresge Hearing Research Institute are among the best in the world and represent a major strength. The Michigan Institute for Clinical and Health Research (MICHR), funded by a Clinical Translational Science Award, sponsors outstanding training opportunities in clinical research as well as resources for clinical research. In addition, the University of Michigan has extensive investments in both clinical and basic research in terms of numerous core facilities, and major cross- departmental centers.
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1 |
2018 — 2019 |
Corfas, Gabriel |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Mouse Models to Test the Roles of Gamma-Secretase-Dependent Erbb4 Nuclear Signaling in Brain Development @ University of Michigan At Ann Arbor
Project Summary The receptor tyrosine kinase (RTK) ErbB4 plays important roles in nervous system development and function, but the mechanisms by which this takes place remain poorly understood. All RTKs exert biological functions through their ?canonical? signaling cascades. Several years ago, we discovered that alternative splicing generates an ErbB4 isoform we named ErbB4-JMa that after sequential cleavage by tumor necrosis factor-?- converting enzyme (TACE) and then by the presenilin 1/?-secretase complex, signals directly to the nucleus through its soluble intracellular domain (sE4ICD). Furthermore, we and others found evidence suggesting that direct ErbB4 nuclear signaling mediates several key steps in brain development. However, these observations were made using cells in culture and mice with complete ErbB4 loss of function. Therefore, the roles of direct ErbB4 nuclear signaling in the intact nervous system remain undefined. To fill this gap in knowledge, we generated new mutant mice to eliminate the generation of sE4ICD without loss of ErbB4 canonical signaling. Specifically, using CRISPR-Cas9 we generated mice in which the ErbB4-JMa isoform has been rendered uncleavable by creating point mutations in the TACE cleavage site, or ErbB4-JMa isoform translation has been specifically eliminated by the introduction of point mutation that creates a premature termination codon. We propose to validate and characterize the effect of these mutations on ErbB4 cleavage and expression (Aim 1) and to determine the consequences of specific loss of ErbB4 nuclear signaling on brain development phenotypes known to be affected by loss of ErbB4 (Aim 2). These studies will not only provide insights into the biological roles of ErbB4, a molecule linked to neurodevelopmental disorders, but will also provide the first animal models that formally interrogate the roles of direct nuclear signaling by a receptor tyrosine kinase in the intact organism and will characterize the impact of a new presenilin-1/?-secretase-dependent signaling pathway on nervous system development in vivo. Given the involvement of presenilin-1/?-secretase in neurodegeneration, the link between ErbB4 nuclear signaling and genomic stability in the nervous system, the results from these studies can bring new insights into the mechanisms of Alzheimer's disease.
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1 |
2019 — 2020 |
Corfas, Gabriel |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Metabolomics and Lipidomics of Noise Induced Hearing Loss @ University of Michigan At Ann Arbor
Project Summary Noise-induced hearing loss (NIHL) has reached epidemic levels in the USA, affecting an estimated 24.4% of adults and up to 17% of youths age 12-19. However, there are currently no treatments to prevent or reverse NIHL, in part because we know remarkably little about how noise damages the inner ear. We hypothesize that understanding the cellular and molecular mechanism by which noise damages the inner ear will help in creating new medicines for NIHL. The effects of noise are usually very rapid, e.g., many are evident immediately after a damaging exposure, suggesting they are mediated by changes in metabolism, which can occur rapidly, as opposed to resulting from effects on gene expression, which can take hours to manifest. Very little is known about the impact of noise on the inner ear metabolome. We believe that defining the effects of noise on the inner ear metabolome will fill a critical gap in knowledge, i.e., how noise damages the inner ear, and could lead to the identification of targets for future therapies. In preliminary proof-of-concept studies, we found that liquid chromatography/mass spectroscopy (LC/MS)-based metabolomics profiling is a powerful approach for the accurate characterization of inner ear metabolites and how these are affected by noise. We used targeted metabolomics on freshly harvested inner ears to define the relative abundance of 220 metabolites, which includes coverage of the major pathways in central carbon metabolism. We found that noise exposure induces acute changes in the inner ear metabolome and that these effects have high statistical significance and consistency. We also found that the impact of noise on the inner ear metabolome depends on the intensity and duration of exposure. Pathway analysis of the altered metabolites suggests that noise exposure activates redox and glutamate pathways. We now propose to develop this methodology further and to explore the effects of noise on the inner ear in an untargeted approach by working on two specific aims. In Aim 1 we will determine the impact of noise on the inner ear by performing untargeted metabolomics and lipidomics in mice with different types of noise exposures. In Aim 2 we will determine the contribution of hair cells and their activity to the noise- induced metabolic changes by testing the effects of noise on the inner ear metabolome and lipidome of mice lacking hair cells or capacity for mechano-transduction.
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1 |
2019 — 2021 |
Corfas, Gabriel |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Symposia For Association For Research in Otolaryngology @ University of Michigan At Ann Arbor
ABSTRACT The Association for Research in Otolaryngology (ARO) is requesting continued support from of an NIDCD Conference Grant for its annual Midwinter Research Meeting (MWM). The MWM is a unique meeting where current basic and clinical research related to otolaryngology is presented. In addition to poster presentations and podium sessions where cutting edge research is presented, the meeting includes symposia and workshops that allow presentation of up-to-date summaries of broad scientific issues that extend beyond the field of otolaryngology. These symposia typically include invited scientists and clinician-scientists from related fields whose work may be relevant to emerging areas of research in otolaryngology. The symposia have been supported by the Conference Grant for more than 30 years and have contributed to the success of the meeting, as evidence by its growth over the years. The growth and development of otolaryngology research depends on bringing young investigators into the field. Travel awards for young investigators, including residents, medical students, and minority pre-doctoral and postdoctoral fellows have been supported by the NIDCD Conference Grant. We request support to continue these activities. In addition, the NIDCD Conference Grant would continue to enhance accessibility of the MWM for individuals with disabilities, particularly those with hearing impairments.
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1 |
2020 |
Corfas, Gabriel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Roles of Neuronal Activity in Peripheral Nerve Myelination @ University of Michigan At Ann Arbor
Project Summary Myelination is critical for normal conduction of action potentials and synchronized transmission of neural impulses. Recent studies have demonstrated that CNS myelin development, maturation and maintenance are regulated by neuronal activity and experience. In contrast, very little is known about how experience and activity regulate myelin development in the PNS, nor how experience-dependent neural activity affects re- myelination after peripheral nerve or glial cell injury in vivo. This is in part due to the difficulty in precisely altering activity of PNS nerves, since they are typically a mixture of both sensory and motor fibers, or of sensory axons mediating different types of modalities. We hypothesize that sensory activity regulates peripheral nerve myelination, myelin maintenance and remyelination, and propose to address this fundamental gap in knowledge using the auditory system as a model. Type I auditory nerve (AN) fibers in the mouse cochlea offer an ideal platform to dissect the role of activity on peripheral myelination because: (a) maturation of AN myelin coincides with auditory function maturation during the first postnatal month, suggesting that activity may affect Schwann cells; (b) re-myelination of AN fibers occurs following Schwann cell ablation; (c) AN myelin dysfunction is associated with hearing deficits, demonstrating a critical role for myelination in cochlear function, particularly in the transmission of key temporal features of sound that are important for understanding speech; (d) we can manipulate the activity of primary auditory neurons by ablating hair cells, by exposing animals to defined auditory experiences, or using genetic tools; (e) we can efficiently isolate and examine the entire peripheral AN at the structural, cellular and molecular levels; and (f) we can assess the impact of myelin defects on cochlear and auditory nerve function in the intact mouse can be assessed at high- resolution with standard electrophysiological techniques. Furthermore, AN axons are myelinated by both Schwann cells (in the distal part) and oligodendrocytes (in the proximal part), permitting a direct comparison of the effects of activity on both types of myelinating cells within the same nerve. We will use mouse models to address this gap in knowledge in three specific aims. In Aim 1, we will use mutants that are defective in hair cell mechanotransduction and synaptic function to determine the role of AN activity in myelination during the neonatal and juvenile time periods. In Aim 2, we will test the roles of auditory experience and NRG1/ErbBR signaling in AN myelination during the neonatal and juvenile periods. Finally, in Aim 3, we will test whether sound-driven neuronal activity modulates AN re-myelination in the mature cochlea. Successful completion of the proposed aims will provide valuable insight into the role of neural activity in PNS myelination and a more precise understanding of the impact of myelin dysfunction on hearing.
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