1987 |
Altschuler, Richard A |
S10Activity Code Description: To make available to institutions with a high concentration of NIH extramural research awards, research instruments which will be used on a shared basis. |
Video Acquisition, Enhancement and Analysis System @ University of Michigan At Ann Arbor
The use of image processing equipment for video enhancement and analysis is necessary to enhance and extend the research of four spearte goups of investigators at the Kresge Hearing Research Institute: It will be used by Dr. Nuttall's group to enhance ongoing NIH funded research into the control of cochlear vasculature. Dr. Nuttall is developing vital microscopy techniques to examine and quantitatively measure the cochlear blood flow response to metabolic demands and other manipulations. The Image I system by IVS will not only enhance the ability to resolve vessel size but will open up new avenues of in vivo microscopy in that will be used in future metabolic studies at the cellular level in the cochlea. It will be use by Dr. Schact's group to enhance ongoing NIH funded research into the role of phosphoinositides in cochlear function, specifically on motile events in isolated outer hair cells. The image enhancement capabilities of the IVS Image I system will be necessary to resolve small changes in hair cell length, while the motion detection and pixel analysis capbilities of the sytem will help to quantitate these changes. It will also evaluate fluorescent markers in the cells. It will be used by Dr. Altschuler's group to investigate the localization of transmitters and the structural basis of outer cell function. Dr. Altschuler has used the IVS Image I in past studies and will need the increased resolution affaorded by this system to examine the distribution of immunoreactive labels in the cochlea. This system can also be used to resolve cochlear hair cell structures related to motility at the electron microscope level, using the GATAN model 622 system to interface to a JEOL 1200 electron microscope and at the LM level (on both regular and isolated hair cells) interfacing to a Leitz photomicroscope through a DAGE/MTI video camera. It will be used by Dr. Carey's group in NIH funded examinations of chromosomal abnormalities in human squamous cell carcinomas The IVS Imaeg I will increase the ability to resolved chromosomes, to identify specific chromosomal abnormalities that commonly occur in this type of cancer and to identify chromosomal markers that characterize individual tumor cell lines. In additiaonlit will enable real-time comparison of normal and malignant cell spreading, migration, and mitosis, as well as analysis with monoclonal markes.
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1 |
1987 — 1989 |
Altschuler, Richard A |
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. |
Gaba &Glycine in the Auditory Brainstem @ University of Michigan At Ann Arbor
auditory pathways; brain stem; glycine; gamma aminobutyrate;
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1 |
1988 — 1989 |
Altschuler, Richard Schacht, Jochen (co-PI) [⬀] Nuttall, Alfred (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Consensus Meeting-June 1988-At Kresge Hearing Research Institute, University of Michigan, Ann Arbor, Michigan 'Current Concepts of Hair Cell Function.' @ University of Michigan Ann Arbor
The sensory cells of the inner ear are called hair cells, and they are responsible for hearing and balance. With modern tools, there has been a new sophistication in analyzing how these receptors work at the cellular level. This conference will bring together biophysicists, biochemists, pharmacologists, physiol- ogists and anatomists to focus on three major topics: hair cell motility, information processing, and intercellular connections among hair cells and nerve cells. The emphasis will be on reaching some consensus on these three topics, since they have recently emerged as leading issues, as the technology to address them has advanced in the last decade. The impact of this meeting is likely to be a new formulation of the role of interactions between the peripheral sensory system and the central nervous system, and will be important to understanding sensory processing in general, as well as understanding auditory and vestibular function in particular.
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0.915 |
1990 — 2000 |
Altschuler, Richard A |
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. |
Amino Acid Neurotransmitters in the Auditory Brainstem @ University of Michigan At Ann Arbor
Neurotransmitters, receptors and their specific pathways and synapses make up the cytochemical substrate of the auditory system. Knowledge of this cytochemical substrate is needed to understand auditory function but is also crucial towards identification and treatment of dysfunctions. We have been working towards the goal of defining this substrate in the lower auditory brainstem for the last ten years, with studies of neurotransmitter candidates including excitatory and inhibitory amino acids and neuropeptides. Our approach has relied on immunocytochemical techniques at the light and electron microscopic levels and antibodies to neurotransmitter candidates, related enzymes, and associated receptors. Many of our studies represent the first examination in the auditory system (often among the first in any system) and recent findings include the first demonstration of GABA and glycine co-localization and of GABAa/BZD receptor heterogeneity. We have also carried out several types of tract tracing studies (anterograde, retrogade and lesion). The proposed studies are to continue towards the goal of defining the cytochemical substrate of the auditory brainstem, addressing the major issues of co-localization of neurotransmitters and receptor heterogeneity and combining tract-tracing and immunocytochemistry. We propose to: 1) investigate the distribution of GABA and glycine immunoreactive terminals in the lower auditory brainstem; determine their relative numbers, which terminals co-contain GABA and glycine and elucidate how GABA, glycine and GABA and glycine co-labeled immunoreactive terminals relate to immunolabeled glycine and GABA receptors, 2)determine the distribution of excitatory amino acid cells and terminals in the lower auditory brainstem using antibodies to glutamate and glutaminase, 3)determine how GABA, glycine and glutamate immunoreactive terminals are distributed on somata and dendritic trees of cochlear nucleus spherical bushy cells and octopus cells, 4)determine the sources and subclasses of GABA, Gly and Glu immunoreactive terminals on defined cells types in ventral cochlear nucleus (CN), lateral superior olive (LSO) and medial nucleus of the trapezoid body (MNTB) through combined immunocytochemical-tract tracing, 5)investigate heterogeneity in the expression of the GABA receptor in defined cell types in the CN using cDNA probes and monoclonal antibodies to the different subunits of the GABA receptor in in situ hybridization and immunocytochemical studies.
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1 |
1990 — 1994 |
Altschuler, Richard A |
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. |
Mechanisms of Age-Related Auditory Sensory Deficits @ University of Michigan At Ann Arbor
Hearing loss related to aging (presbyacusis) is one of the major disorders affecting the elderly, yet we know very little about what causes the changes that occur in the auditory system and how these relate to hearing loss. Is human presbyacusis simply an aging of auditory structures, is it aging plus the summing of a lifetime of ototraumatic insults from noise, chemicals (drugs), and disease or are other factors such as changes in blood flow, increased free radical formation, genetically programmed neuronal cell death, increased susceptibility to noise or chemical damage or even diet significant? Is human presbyacusis not the result of "pure aging" of auditory structures and this the reason no adequate animal model has been found? We have established a collaborative effort between the laboratories of anatomy, biochemistry and physiology of the Kresge Hearing Research Institute to elucidate mechanisms involved in the development of auditory sensory deficits in aging. We will perform morphological and neurochemical assessments in guinea pig and rat to test the following hypotheses: 1) That age-related loss of spiral ganglion cells and changes in inhibitory and excitatory circuitry in auditory brainstem and cochlea occur independently of changes in organ of Corti, 2) That there are age- related changes in cochlear blood flow, cochlear vessels and cochlear vascular reactivity, 3) That changes in the sensitivity of cochlear hair cells to ototraumatic insults occur with aging, 4) That free radical accumulation induces changes in lipid peroxidation, membrane lipid domains, membrane fluidity and function in aging, and 5) That increased fat and/or cholesterol diet influences the age-related changes listed above. Physiological assessments of auditory function will be performed for correlation with these parameters. This will provide us with information that will help us not only to better understand the origins and development of hearing loss in the elderly, but, to develop more effective methods of its treatment and prevention.
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1 |
1990 |
Altschuler, Richard A |
S10Activity Code Description: To make available to institutions with a high concentration of NIH extramural research awards, research instruments which will be used on a shared basis. |
Laser Scanning Confocal Microscope With Image Processing @ University of Michigan At Ann Arbor
This proposal requests a laser scanning confocal microscope (LSCM) and image processing workstation for a group of 9 majors users and 3 minor users in six departments at the University of Michigan (& one department at Ohio University). The LSCM with image analysis will also provide an important resource for the university at large. LSCM provides a major improvement over conventional light microscopy, particularly for fluorescence imaging, with 1) increased resolution, 2) increased contrast, 3) increased fluorescence sensitivity and detectability, 4) elimination of stray light and fluorescence scatter, 5) ability to achieve features 1-4 in thick sections or specimens along with optical sectioning. In fluorescent applications, the rapid movement and short excitation time of the finely focused laser beam provide for less bleaching, less toxicity from free radical formation (important in living material) and no piping (in cylindrical cells) in addition to elimination of scatter. Increased resolution and contrast, as well as optical sectioning is also possible from Golgi stained material. Image processing is necessary to achieve any image from LSCM. Construction of 3-D images from optical sectioning and interactive tilting, rotating, slicing, and image enhancement is possible with an appropriately powerful computer workstation. LSCM with 3-D image processing provides an improved ability to analyze the morphological appearance, location and distribution of the label. These features are critical to the needs of the user group and their research programs.
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1 |
1996 |
Altschuler, Richard A |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Molecular Mechanisms of Central Auditory Plasticity @ University of Michigan At Ann Arbor |
1 |
1997 — 2002 |
Altschuler, Richard A |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. 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--Histology @ University of Michigan At Ann Arbor
histology; biomedical facility; cochlea; electron microscopy; in situ hybridization; immunocytochemistry;
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1 |
1997 — 2001 |
Altschuler, Richard A |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Molecular Mechanisms of Protection @ University of Michigan At Ann Arbor
neuroprotectants; stress proteins; noise biological effect; gene induction /repression; cochlea; oligonucleotides; antisense nucleic acid; genetically modified animals; laboratory mouse;
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1 |
1997 |
Altschuler, Richard A |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Histological Visualization &Assessment @ University of Michigan At Ann Arbor
technology /technique development; animal tissue; prosthesis; nervous system; hearing; ear; biomedical resource; bioengineering /biomedical engineering; biomaterials; Mammalia;
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1 |
1998 |
Altschuler, Richard A |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Histological Visualization &Assessment: Probe Reaction W/ Tissue @ University of Michigan At Ann Arbor
A critical component of implantable micro-probe development and in vivo testing is the assessment of the probe in its tissue environment, which we term the morphological substrate of function. This helps to determine if the probe is causing any damage to the surrounding tissue. Just as importantly, it allows one to identify and characterize the cellular elements in the tissue that are interacting with the probe. The objectives in this project are to increase our ability to assess the interaction of the probe with its tissue substrate both in the recording mode and for stimulation. Our first objective is to further characterize the cells the probe is recording from by combining physical information with geometric information in hopes of identifying the actual cells involved in chronic recordings. For stimulation experiments, we hope to better characterize tissue reaction to the probe and to the charge flow introduced through chronic electrical stimulation. Our second objective is to generate quantitative information on cellular elements. This will allow us to characterize and compare tissue reaction with different probes and different conditions as well as to better define the normal environment the probe is operating in. Finally, our third objective is to assess and visualize in three dimensions which will support objectives on other project which involve modeling of complex patterns of tissue reaction surrounding the probe structures. All of these objectives will provide valuable feedback towards improving electrode designs.
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1 |
1999 |
Altschuler, Richard A |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Central Auditory Functional Diversity and Plasticity @ University of Michigan At Ann Arbor
This proposal is for funding a 2 + day conference on "Molecular Mechanisms in Central Auditory Functional Diversity & Plasticity". The purpose is to present recent developments in this new exciting area of research and to generate discussions, identify areas of consensus and, where there is a disagreement, to engender correlation between results from different approaches. It will also provide opportunity for interactions between investigators leading to new ideas, new approaches and potential collaborations. The conference is planned for June 1999 in a resort/conference center (during the off season) in Park City, Utah (35 minutes from the international airport at Salt Lake City). There will be approximately 40 invited speakers, including three from outside the auditory field talking about molecular mechanisms, functional diversity and plasticity, respectively, and two speakers lecturing about molecular genetics. There will also be six international speakers. These invited speakers will form a core audience with an estimated fifty additional participants to be drawn from publicity mailings to the membership of the Association for Research in Otolaryngology and the Society for Neurosciences. The meeting will consist of presentations by invited speakers, and a poster session. The first part of the meting will focus on presenting and discussing the molecular mechanism underlying neurotransmission in the central auditory system and how these molecular mechanisms shape individual neuronal response properties. There will then be a session on the molecular genetics of central auditory function and disorders. The final session will be on the molecular bases of central auditory plasticity and disorders such as tinnitus, age-related hearing loss and noise induced hearing loss.
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1 |
2000 — 2002 |
Altschuler, Richard A |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Histological Visualization &Assessment: Confocal Microscopy @ University of Michigan At Ann Arbor
A critical component of implantable micro-probe development and in vivo testing is the assessment of the probe in its tissue environment, which we term the morphological substrate of function. This helps to determine if the probe is causing any damage to the surrounding tissue. Just as importantly, it allows one to identify and characterize the cellular elements in the tissue that are interacting with the probe. The objectives in this project are to increase our ability to assess the interaction of the probe with its tissue substrate both in the recording mode and for stimulation. Our first objective is to further characterize the cells the probe is recording from by combining physical information with geometric information in hopes of identifying the actual cells involved in chronic recordings. For stimulation experiments, we hope to better characterize tissue reaction to the probe and to the charge flow introduced through chronic electrical stimulation. Our second objective is to generate quantitative information on cellular elements. This will allow us to characterize and compare tissue reaction with different probes and different conditions as well as to better define the normal environment the probe is operating in. Finally, our third objective is to assess and visualize in three dimensions which will support objectives on other project which involve modeling of complex patterns of tissue reaction surrounding the probe structures. All of these objectives will provide valuable feedback towards improving electrode designs.
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1 |
2002 — 2006 |
Altschuler, Richard A |
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. |
Amino Acid Transmitters in the Auditory Brainstem @ University of Michigan At Ann Arbor
Results now show a diversity in amino acid transmitters and receptor subunits that provide for the specialized shaping of neuronal responses and that their changes can underlie auditory brain stem plasticity. Our first Specific Aim is based on our finding decreased GABA release and correlated decreased inhibition in the inferior colliculus (IC) 3 weeks following deafness. It uses immunocytochemistry and tract tracing to test the hypotheses that decreased GABA release is a consequence of decreased GABA in terminals, with a specific GABA sub-circuit to the IC effected, rather than a "global" decrease in all inputs. Caspary's group found GABA-A receptor subunit changes that correlated with age-related hearing loss, but couldn't differentiate "pure aging" versus "deafness". Our second specific aim uses quantitative in situ hybridization to test if there will be comparable subunit changes in our more "pure deafness" model, as well as changes in glycine receptor subunits in the DCN where a glycine mediated decrease in inhibition is found. We further hypothesize correlation between changes in transmitter and receptor. We predict GABA but not glycine receptor subunit changes in the CIC and glycine but not GABA receptor subunit changes in fusiform cells. Studies will also uses receptor autoradiography to test a functional correlate, ligand binding. Our final specific aim uses gene micro arrays to screen for differential expression following deafness and test the hypothesis that deafness induces decreased expression of presynaptic neurotransmitter- related genes and compensatory expression of post-synaptic genes. It then uses quantitative in situ hybridization to test the hypothesis that changes will be specific to distinct neuron types. These studies will provide new information on the role of transmitters and receptors in central auditory plasticity. This will, in turn, increase our understanding of the molecular basis of central auditory system dysfunction and provide clues for interventions that might help improve the re-introduction of hearing following deafness, currently with cochlear prostheses and in the future after hair cell regeneration.
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1 |
2003 — 2004 |
Altschuler, Richard A |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Molecular Mechanisms in Central Auditory Function, @ University of Michigan At Ann Arbor |
1 |
2004 |
Altschuler, Richard A |
R55Activity Code Description: Undocumented code - click on the grant title for more information. |
Stress Response Pathways in the Rodent Cochlea @ University of Michigan At Ann Arbor
Cell stress or trauma can induce intracellular "survival" pathways that bring cells and systems back to "normal" following the stress and/or induce apoptosis pathways for controlled cell death. Different levels of stress can induce different pathways. The long-term goal of our studies is to develop interventions that can change the balance in the stress response of the cochlea towards the pathways that lead to protection, repair and recovery, thus reducing acquired deafness. The short-term goal is to determine the molecular mechanisms underlying the "protective" heat shock protein (Hsp) pathway in the cochlea. The first specific aim examines if Hsf1, the Transcription Factor (TF) regulating the Hsp pathway, is activated by noise in a close dependent fashion and when TFs for other protective or cell death pathways are co-activated. The second specific aim tests the role of the Hsf1 - hsp pathway in protection in the cochlea, by determining if there is decreased protection and/or recovery from noise in Hsf1 knock out (KO) mice and increased protection in transgenic mice with Hsf1 overexpression. It also examines if enhanced protection from prior exposure to heat or noise is still present in the Hsf1 KO mice. The third specific aim examines downstream targets in the Hsf1 pathway and tests their induction in the cochlea and relation to Hsf1 in the KO mice. The final specific aim examines hsp27, in which phosphorylation of the constitutive pool has been shown to play a protective role in other systems through regulation of actin. These studies will provide increased understanding of the hsp stress response in the cochlea and its interplay with other protective versus apoptotic pathways. They will generate a rational mechanistic framework for future studies on interventions to reduce acquired deafness.
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1 |
2005 — 2009 |
Altschuler, Richard A |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Core--Otopathology and Histology @ University of Michigan At Ann Arbor
The purpose of the Otopathology/Histology Core is to provide expertise as well as coordinated and uniform assessments and experimental approaches for the histological methods common to Projects 0001, 0002 & 0003. The first aim is to determine the otopathology (histological changes) for Projects 0001, 0002 & 0003 to complement the functional assessments of hearing carried out in the Auditory Physiology Core. This will b accomplished with surface Preparations as a quantitative assessment of presence or absence of inner hair cells and outer hair cells (in all three rows) by position along the cochlear spiral. Data is viewed as a graph (cytocochleogram) and also provided as a percentage present at every location (observation point) in every cochlea. Furthermore, plastic para-modiolar sections are used for assessment of otopathology and age related changes for all cellular elements in the cochlea, including organ of Corti, auditory nerve/spiral ganglion cells and their peripheral processes, stria vascularis and lateral wall. Assessments are quantitative (Spiral ganglion cell numbers, strial width/thickness) and qualitative descriptions of pathological changes. The second aim is to determine the cellular localization of gene expression and proteins. Immunocytochemistry will be used for protein localization and in situ hybridization will be used to localize gene expression to specific cochlear cell types. Immunocytochemistry is performed on paramodiolar cryostat sections of the whole cochlea that allow immunostaining of all major cellular elements. Immunocytochemistry on surface preparations is used to provide additional "three dimensional" resolution of immunolocalization details in the organ of Corti. In situ hybridization is used to localize gene expression to specific cochlear cell types, performed on paramodiolar cryostat sections of the whole cochlea. Data will be reported to the Data Management and evaluated and discussed with all investigators.
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1 |
2007 — 2011 |
Altschuler, Richard A |
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. |
Cell and Molecular Biology Core
The goal of the Cell &Molecular Biology (CMB) Core is to enhance and extend the quality and scope of individual research projects, by providing access to molecular technologies and measures that will yield insights into the molecular basis for hearing and hearing impairment. To achieve this goal the CMB Core has Specific Aims that fall into four areas: Development, Education, Collaboration and Service. In Development, the CMB will bring new methods and approaches to individual investigators and develop technology and data bases to facilitate use of the mouse model. In Education, the CMB will provide information on new advances in methodology to individual investigators, train staff of individual investigators in both routine and novel molecular methodologies, provide a bridge to centralized University of Michigan facilities for novel and advanced methodologies, and hold monthly meetings of Core Discussion Group with outside experts on specific topics to introduce new methods and approaches, share experiences, problems and successes and develop new productive collaborations. This last goal will be expanded In Collaborations, in which the CMB will bring new investigators to the study of hearing and balance research, bring in outside experts for new directions and approaches, and provide a format for discussions leading to new areas and directions of research. For Service, the CMB will provide state-of-the-art support for morphological and molecular assessments, provide assistance in integration of morphological and molecular assessments, provide normative data bases and provide assistance in experimental design and interpretation of results. The CMB Core will also work closely with the Physiology Core and the Delivery Core to coordinate physiological and morphological characterization of animals at both the molecular and systems level to enhance our understanding of hearing and to define molecular interventions that will prevent and treat hearing loss.
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1 |
2007 — 2011 |
Altschuler, Richard A |
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. |
Physiological and Behavioral Assessment of Lateral Efferent Function
DESCRIPTION (provided by applicant): Lateral olivocochlear (LOG) efferent endings on Type I auditory nerve (AN) peripheral processes are strategically placed to provide a powerful and dynamic regulation of AN activity. We have developed methods to lesion the LOG which allowed our lab and others to show changes in auditory evoked potential (CAP, ABR) amplitudes that could specifically be attributed to the loss of LOG innervation. This has led us to hypothesize that the LOG acts on auditory nerve peripheral processes to increase dynamic range across AN fibers, which in turn has the function of improving intensity discrimination. Our proposed specific aims test this hypothesis using MPTP to transiently disrupt LOG processes in the cochlea, without disrupting afferents or the central auditory pathways. Specific Aim 1 uses electron microscopy, immunocytochemistry and whole nerve recording to test the hypothesis that LOG disruption by MPTP will (H1a) induce a transient LOG specific loss of fibers and terminals whose loss will (H1b) result in decreases in AN spontaneous activity, adaptation and dynamic range. (H1c) A greater morphological disruption will correlate with more effect on AN responses. Specific Aim 2 is based on preliminary results that show that when LOG efferents co-contain both DA and other neurotransmitters, immunolabeling for both decreases following MPTP application. This leads us to hypothesize (H2) that dopamine and other LOG transmitters can be "co-disrupted" by MPTP when they are co-contained in the same fiber, including disruption of neurotransmitters believed to be excitatory. Specific Aim 3 uses single unit AN recording to test the hypothesis that disruption of the LOG innervation of the cochlea will (H3a) suppress spontaneous AN activity, (H3b) alter sound-induced responses of AN, and (H3c) reduce tonic adaptation of AN, resulting in a "redistribution" of the proportion of High (H), Medium (M) and Low (L) spontaneous rate (SR) fibers Specific Aim 4 uses behavioral psychophysics to test the hypotheses that MPTP-induced disruption of LOG efferents will (H4a) alter dynamic range for perceived loudness of signals and (H4b) decrease acuity for intensity-related psychophysical discrimination tasks. (H4c) MPTP will have no effect on frequency discrimination These studies will increase our knowledge of mechanisms of LOG action at the first synaptic complex in the cochlea. They will test the LOG contribution to loudness perception and intensity discrimination. As such there will be clinical relevance towards interventions to protect AN from excitotoxic injury (from noise) and treatment of "cocktail party syndrome" and similar processing disorders, where the LOG may play an important role in detecting signals in a noisy background.
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1 |
2010 |
Altschuler, Richard A |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Pathology of the Inner Ear: Mechanisms and Treatment
DESCRIPTION (provided by applicant): In the last decade we have witnessed exciting advances in the prevention and rehabilitation of otopathologies. An increased understanding of underlying mechanisms is rapidly leading to the development of novel and effective interventions. For the first time, clinical trials on the prevention of drug- and noise-induced hearing loss have either been recently concluded or are under way. The most effective current rehabilitation, cochlear prostheses, has matured and is expanding to new horizons, while alternate treatment paradigms, involving molecular medicine, begin to show promise in animal experiments. It is therefore timely to have a meeting bringing together basic, translational and clinical researchers as well as clinicians to critically review these developments and look to the future. We propose a two day meeting with platform presentations, posters and time for formal and informal discussions to: 1) Provide an understanding of molecular mechanisms underlying widespread and unresolved otopathologies;2) analyze these mechanisms for common themes as well as differences;3) explore how an understanding of basic principles can be used to develop targeted treatments;4) familiarize researchers and clinicians with each others'goals and problems, 5) discuss opportunities to accelerate the translation of basic research to the clinic and 6) create awareness in students, residents and trainees about inner ear disorders and the state of the art of research and clinical endeavors to establish a basis for future careers and collaborations. A primary objective of this conference is to increase the dialogue and cross-fertilization across disciplines and pathologies. The speakers, therefore, represent and will present basic research, translational research and clinical considerations. Furthermore, in addition to a multidisciplinary presentation of recent and relevant results, a purpose of the meeting will be to encourage discussions with the wider auditory, vestibular and clinical community, for which the poster sessions will be an appropriate vehicle. Together with a later publication of reviews and articles by speakers and selected poster presenters in a special issue of Hearing Research, the conference will identify areas of consensus and disagreement, generate new ideas and areas for future development, provide opportunity for cooperation and stimulate translation of research results to clinical and even potential commercial application. PUBLIC HEALTH RELEVANCE: Recent developments in our understanding of the mechanisms underlying some of the most common inner ear pathologies, their prevention and their treatment have made it timely to have a meeting bringing together basic, translational and clinical researchers as well as clinicians to critically review these developments and look to the future. We propose a two day meeting to provide an understanding of molecular mechanisms, to analyze mechanisms for common themes across different inner ear pathologies as well as differences and to examine developments in targeted interventions for prevention and treatment across inner ear disorders.
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1 |
2011 |
Altschuler, Richard A |
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. |
Hearing Preservation For Noise or Cochlear Implantation: Mechanisms &Treatments
DESCRIPTION (provided by applicant): One of the most exciting advances in the last decade has been the development of therapies to preserve hearing under conditions of stress that can otherwise cause hair cell loss. Current therapies, however, focus on preservation of sensory cells and recent results (Kujawa and Liberman, 2006, 2009) indicate that the connections between inner hair cells (IHC) and auditory nerve (AN) may also be at risk for permanent loss. Our proposed studies examine loss of IHC-AN connections during two stresses chosen for high clinical relevance: Noise Induced Hearing Loss and Prostheses Insertion in Ears with Remaining Hearing, then test the efficacy of anti-oxidant (AO) therapy for protection / recovery and finally determine if adding anti- excitotoxicity therapy to the AO therapy will improve protection / recovery of IHC-AN connections and hearing. Aim 1-Test the hypothesis that a moderate noise causing permanent loss of many hair cells will also produce a permanent loss of many IHC-AN connections on remaining IHCs and later loss of auditory neurons (SGN). Aim 2- Test the hypothesis (2a) that AO treatments that effectively reduce noise-induced hair cell loss will be less effective in reducing the loss of IHC-AN connections and (2b) that adding a specific anti-excitotoxicity therapy will improve preservation of IHC-AN connections, long term survival of SGN and hearing. Aim 3 - Test the hypothesis that trauma from insertion of a prostheses into a hearing ear will induce loss of IHC-AN connections, including in regions where hair cells are not lost. Aim 4 - Test the hypothesis (4a) that adding AO treatment will be more effective in preserving hair cells than IHC-AN connections from the trauma of prostheses insertion and (4b) addition of specific anti-excitotoxicity therapy to the AO therapy will improve the preservation of IHC-AN connections. Aim 5 - Test the hypothesis that reducing loss of IHC-AN connections and SGN will improve acoustic hearing and spatial and temporal acuity of psychophysical responses to cochlear implant stimulation. Results of the proposed studies will redefine and broaden treatment targets for preserving hearing with high impact not only toward treating the two conditions being tested, noise-induced hearing loss and implantation of cochlear prostheses into ears with remaining hearing, but with high relevance towards best treatment practices for other inner ear pathologies ranging from ototoxicity to vestibular disorders. If successful, a new treatment paradigm can be directly translated to clinical trials and benefit millions of individuals worldwide.
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1 |
2012 — 2015 |
Altschuler, Richard A |
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. |
Hearing Preservation For Noise or Cochlear Implantation: Mechanisms & Treatments
DESCRIPTION (provided by applicant): One of the most exciting advances in the last decade has been the development of therapies to preserve hearing under conditions of stress that can otherwise cause hair cell loss. Current therapies, however, focus on preservation of sensory cells and recent results (Kujawa and Liberman, 2006, 2009) indicate that the connections between inner hair cells (IHC) and auditory nerve (AN) may also be at risk for permanent loss. Our proposed studies examine loss of IHC-AN connections during two stresses chosen for high clinical relevance: Noise Induced Hearing Loss and Prostheses Insertion in Ears with Remaining Hearing, then test the efficacy of anti-oxidant (AO) therapy for protection / recovery and finally determine if adding anti- excitotoxicity therapy to the AO therapy will improve protection / recovery of IHC-AN connections and hearing. Aim 1-Test the hypothesis that a moderate noise causing permanent loss of many hair cells will also produce a permanent loss of many IHC-AN connections on remaining IHCs and later loss of auditory neurons (SGN). Aim 2- Test the hypothesis (2a) that AO treatments that effectively reduce noise-induced hair cell loss will be less effective in reducing the loss of IHC-AN connections and (2b) that adding a specific anti-excitotoxicity therapy will improve preservation of IHC-AN connections, long term survival of SGN and hearing. Aim 3 - Test the hypothesis that trauma from insertion of a prostheses into a hearing ear will induce loss of IHC-AN connections, including in regions where hair cells are not lost. Aim 4 - Test the hypothesis (4a) that adding AO treatment will be more effective in preserving hair cells than IHC-AN connections from the trauma of prostheses insertion and (4b) addition of specific anti-excitotoxicity therapy to the AO therapy will improve the preservation of IHC-AN connections. Aim 5 - Test the hypothesis that reducing loss of IHC-AN connections and SGN will improve acoustic hearing and spatial and temporal acuity of psychophysical responses to cochlear implant stimulation. Results of the proposed studies will redefine and broaden treatment targets for preserving hearing with high impact not only toward treating the two conditions being tested, noise-induced hearing loss and implantation of cochlear prostheses into ears with remaining hearing, but with high relevance towards best treatment practices for other inner ear pathologies ranging from ototoxicity to vestibular disorders. If successful, a new treatment paradigm can be directly translated to clinical trials and benefit millions of individuals worldwide. PUBLIC HEALTH RELEVANCE: Our proposed studies are to develop and test better treatments to preserve hearing during two traumatic stresses to the ear, chosen for high clinical relevance: Noise Induced Hearing Loss and Prostheses Insertion in Ears with Remaining Hearing.
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2012 — 2016 |
Altschuler, Richard A |
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. |
Hearing, Balance and Chemical Senses Research Core Center
DESCRIPTION (provided by applicant): This application requests support to continue the productive work of the Hearing, Balance and Chemical Senses Research Core Center to enhance the quality and scope of NIDCD-mission oriented research. The proposal builds on experience gained from the two previous P30 grant periods including the successful introduction of the Scientific Synergy Core (Core A) a novel approach to foster interactions and collaborations among scientists at the University of Michigan, Michigan State University, Wayne State University, and University of Toledo. A new development is a broadening of the Core, adding services in the vestibular system and the chemical senses and bringing in investigators studying speech and language pathology. Investigators will continue to be supported by two scientific cores offering resources, training, and services in physiology and behavior (Core B) and cell and molecular biology (Core C). The Instrument Design and Technical Services Core (Core D) will design and manufacture specialized electronic and mechanical instruments as well as consult in computing-related issues. Cores will be supervised by expert core directors and staffed with experienced personnel. The key aims across all the Cores remain to: Aim 1: Enhance and extend the quality and scope of the individual research projects of Core participants. Aim 2: Improve efficiency and productivity of research within the user group. Aim 3: Develop methods and approaches to meet current user needs and to anticipate future needs. Aim 4: Provide education, develop collaborations and bring new people into the field. Within the intellectual environment generated by the Scientific Synergy Core and the availability of these resources, this Center will promote interactions and multidisciplinary research by providing novel methodologies, standardized analytical tools, and the exchange of technological experience. It will continue to generate new users and collaborations attracted by the Core services and interactions. Regular meetings of the core users, the affinity groups, and the entire Center research community will assure the best possible implementation of collaborations and effective use of research support.
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2012 — 2016 |
Altschuler, Richard A |
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 & Molecular Biology Core
This application requests support to continue the productive work of the University of Michigan Cell & Molecular Biology (CMB) Core to enhance NIDCD-mission oriented research. The proposal builds on experience gained from the two previous P30 grant periods The Cell & Molecular Biology (CMB) Core will continue to serve the user base through its four aims: Aim 1: Enhance and extend the quality and scope of the individual research projects of Core participants Aim 2: Improve efficiency and productivity of research within the user group Aim 3: Develop methods and approaches to meet current user needs and to anticipate future needs Aim 4: Provide education, develop collaborations and bring new people into the field New to the next five years, the CMB Core is adding processing and assessment of vestibular tissues and tissues associated with the chemical senses, to reflect the needs of the user base. Dr. Kohrman is replacing Dr. Lomax as the co-Director and the molecular biology consultation offered can expand to include information on developing and using transgenic mice. The CMB will continue to bring new methods and approaches to individual investigators and develop technology, data bases and shared resources. It will provide information on new advances in methodology to individual investigators, train staff of individual investigators in both routine and novel molecular methodologies and provide a bridge to centralized University of Michigan facilities for novel and advanced methodologies. It will provide state-of-the-art support for morphological and molecular assessments, provide normative data bases and provide assistance in experimental design and interpretation of results. It will use the Scientific Synergy Core and periodic meetings with qualified users to present new methods and approaches, share experiences, problems and successes and develop new productive collaborations. The CMB services and presentations will continue to bring new investigators to the study of hearing, balance and chemical senses research. The CMB Core will also work closely with the Physiology Core to coordinate physiological, behavioral, morphological and molecular characterization of animals to enhance our understanding of hearing, balance and chemical senses and to define molecular interventions that will prevent and treat their disorders.
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2012 — 2016 |
Altschuler, Richard A |
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. |
Administrative Shell
The administrative shell has an organizational rather than a scientific focus. While the goals of the individual Cores are to serve the user base, the goal of the administrative shell is to serve the individual cores, overarching needs and the overall Research Core Center mission. The charge to the administrative shell is therefore to: Specific Aim 1: Integrate and supervise the Research Core Center activities Specific Aim 2: Facilitate the operation of the individual cores by resolving issues of space and facilities Specific Aim 3: Assume administrative tasks for all cores such as personnel management and financial operations Specific Aim 4: Carry out or facilitate contacts with University of Michigan administration and granting agencies Specific Aim 5: Coordinate and facilitate the submission of progress reports and renewal grant applications Specific Aim 6: Track user group research and publications associated with their use of the Core Specific Aim 7: Coordinate training across Core components Specific Aim 8: Coordinate and maintain the Research Core Center web site
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2016 — 2019 |
Altschuler, Richard A Stuenkel, Edward L [⬀] |
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. |
Early Stage Training in the Neurosciences
? DESCRIPTION (provided by applicant): This application is a request for continuing support of our training grant, 'Early Stage Training in the Neurosciences' (ESTN), which was founded at The University of Michigan (UM) in 2001. This grant serves as a centerpiece of the Neuroscience Graduate Program's (NGP) training, whose goal is to support broad predoctoral training of exceptional researchers in neuroscience toward careers that address the nation's basic science and biomedical research needs. To be eligible for ESTN support, students must gain admittance to the NGP, which is the most selective biomedical science department/program at the University of Michigan, through either direct or PIBS admission. The ESTN consists of 79 faculty representing 24 departments in 5 schools or colleges. The wide academic distribution, strong research funding and high-level of peer recognition of the ESTN faculty excellently matches this application's focus on broad early stage training in neuroscience. In light of the NGPs growth in training activity, resources, serving as the nexus of cross- disciplinary neuroscience training at the University and the strong institutional commitment we request 9 students be supported by the ESTN. In the first year, students complete a broad-based neuroscience curriculum that includes: neuroscience bootcamp, principles of neuroscience, human neuroanatomy, statistics, research responsibility and ethics, and neuroscience research seminar, in addition to performing two to three research rotations. ESTN trainees are exposed to a broad range of research areas including: Molecular and Cellular Neuroscience; Developmental Neuroscience; Sensory Neuroscience; Cognitive Neuroscience; Behavioral and Systems Neuroscience; Computational Neuroscience; and Clinical Neuroscience. During their second year, students take elective courses, give a research seminar presentation, complete a candidacy examination and begin work on their doctoral thesis. The NGP at University of Michigan is quite proud of its strong history of recruiting and training underrepresented minority students. Our accomplishments and a detailed plan for advancing activity to recruit, retain and develop successful underrepresented minority Ph.D.'s in neuroscience research is highlighted. We also present plans on external and internal evaluation of the program and for instruction in the responsible conduct of research. The NGP organizes a growing number of specific activities towards the goal of improving graduate training of its students so as to create an interactive, supportive and cohesive neuroscience community that successfully facilitates intellectual and research-intensive training. In addition, it has mentored trainees in the importance of grant writing, which has led to considerable success in their reception of external research fellowships. Upon completion of their training, our graduates are poised to tackle a host of basic neuroscience and/or public health issues ranging from the molecular basis of neurodegenerative disorders to brain circuit abnormalities in psychiatric disease. This ESTN grant is critical to the success of the Neuroscience Graduate Program's training mission.
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