1985 — 1989 |
Perl, Edward R |
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. |
Recovery and Regeneration After Neuron Injury @ University of North Carolina Chapel Hill
This program of projects is a continuing investigation of the effects of injury to spinal nerves or to spinal cord tracts upon the functional organization of vertebrate spinal neurons. The overall goal of this program is to provide data on the degree that functionally-effective regeneration or reorganization of spinal neurons and their connections can take place in immature or mature vertebrate nervous systems. Each of the projects has its counterpart or point of departure in deficits suffered by human beings after disease or traumatic injury of the spinal cord and/or of the nervous processes of spinal neurons. The approaches are interdisciplinary and employ animal models in which combinations of physiological, morphological, biochemical and behavioral measures are combined in various ways to test for examples of: a) regeneration or reorganization of spinal pathways in vertebrates, b) changes in the organization of spinal reflexes involving the kidney and bladder after spinal cord injury, c) conditions favoring functionally effective reinnervation of the urinary bladder by foreign nerves, d) factors associated with the specificity of reinnervation and regeneration after injury of sympathetic preganglionic neurons, e) changes in utilization of amino acids and associated modification in cytoskeletal protein synthesis by motoneuron cell bodies after injury of their axons, f) modifications of the projections into the spinal cord of thin afferent fibers after injury of dorsal roots and associated alterations in functional properties of neurons in laminae I and II, and g) modifications in the distribution of chemical markers for primary afferent fibers such as peptides in the spinal gray matter after injury of ascending spinal pathways.
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1985 — 2008 |
Perl, Edward R |
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. |
Spinal and Projection Mechanisms Related to Pain @ University of North Carolina Chapel Hill
DESCRIPTION: This application for renewed support is directed at normal and pathological functional arrangements associated with primary afferent neurons with thin fibers, a population known to be of major importance for pain, temperature sense and related reactions. The overall goals are for better fundamental understanding of the underlying neural functioning and to thereby provide improved strategies for pain management. The proposed work focuses upon two issues. 1) one phase of the work deals with the nature of interconnections among neurons of the superficial dorsal horn (SDH), the region receiving a principal input from the thin, largely nocireceptive, primary afferent fibers. The aim for this phase of the work is to determine the nature of synaptic connections between neurons of the region and the relationship of these connections to input from the primary afferent fibers. The experiments will be done in vitro on spinal cord slices with attached dorsal roots acutely prepared from purpose-bred rodents (hamster, rat). Whole cell, tight-seal recordings are to be used to obtain low noise recording from one or simultaneously from two SDH neurons to study interactions between activity produced by primary afferent fibers, by focal SDH stimuli and by the neurons themselves. The experiments will also explore the importance of purine agents such as ATP and adenosine as synaptic mediators between neural elements of this part of the spinal cord as evidenced by the action of selective pharmacological antagonists and agonists. 2) A second project is directed at processes associated with the novel development of sympathetic adrenergic excitation by cutaneous nociceptors after partial nerve injury and the influence of neurotrophins or other cytokines on them. The latter experiments involve in vitro whole-cell recordings from DRG neurons I) acutely dissociated and cultured from adult purpose-bred rats, ii) acutely dissociated from adult rats with prior nerve injury and iii) dissociated from immature rats at several stages during development. Chemically-defined media will be used for culture to permit the addition or removal of factors possibly influencing the expression of the excitatory adrenergic action.
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1986 — 1990 |
Perl, Edward R |
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 Correlates of Neuronal Function @ University of North Carolina Chapel Hill
We propose new approaches to establishing molecular correlates of functional and structural features of mammalian dorsal root ganglion and hippocampal neurons. The focus will be upon a) neurons of these two populations that employ multiple synaptic mediators, and b) the manner in which key molecular determinants are modulated. The specific aims are: 1) to determine molecular features of primary afferent and hippocampal neurons that distinguish between functional and/or morphological subclasses; 2) to determine the parts played by peptides and other chemical mediators in the function of primary afferent and hippocampal neurons; 3) to examine the biochemical mechanisms underlying modulation of membrane receptors and channels, and the possible coupling of such events to expression of neuron-specific molecular determinants. The experiments will be done in vivo, in cultures of the dorsal root ganglia and hippocampal neurons and in hippocampal slices. Established morphological (light and electron microscopic) and electrophysiological (microelectrode and patch clamp) techniques are to be coupled with immunocytochemical, biochemical, pharmacological and molecular genetic approaches. A facility for the generation of specific polyclonal and monoclonal antibodies and for in situ hybridization histochemistry will be set up for common use by the four projects.
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1990 — 1993 |
Perl, Edward R |
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. |
Recovery &Regeneration After Spinal Neuron Injury @ University of North Carolina Chapel Hill
Renewal of support for five years is requested for a program of research related to injury of neurons of the vertebrate spinal cord. The general goal of this program project continues to be to gain insight into the nature of the fundamental mechanisms associated with regeneration of neurites and/or functional recovery after injury to spinal cord neurons. The projects address issues ranging from functional recovery in cold blooded vertebrates to mammalian models of clinical syndromes. The projects are multidisciplinary in approach, combining physiological. morphological and histochemical/molecular techniques. Most of the projects derive from results obtained during previous years of support. Three of the projects (2, 3, and 6) are directed at the nature or bases of changes in motor function, skeletal or autonomic. After injury of spinal neurons. Two projects (1 and 2) concern the mechanisms if altered sensory function following injury to central or peripheral afferent pathways. One project (5) examines the possibility that causalgic states following periphoral nerve injury may result from altered interactions between synpathetic efferents and nociceptive afferents. While each of the six projects will be carried out by an independent team of investigators, the teams share a common interest in the consequences of injury to spinal neurons, use many of the same techniques, and depend on core facilities to accomplish their research goals.
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1993 — 1996 |
Perl, Edward R |
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. |
Possible Neuropathic Origin of Interstitial Cystitis @ University of North Carolina Chapel Hill
This proposal is aimed at the etiology of a syndrome largely appearing in women, interstitial cystitis (I.C.). The impetus for the study comes from the prominence of sensory symptoms in this syndrome and a predominant occurrence of I.C. in women who may have suffered traumatic injury of pelvic structures by childbearing or pelvic disease. The possibility that neural damage in the pelvic region can lead to an autonomic neuropathy affecting sensory fibers in some way comparable to the somatic syndrome, causalgia, is to be explored. The effects produced by autonomic efferent activity on bladder afferents are to be tested and how partial denervation modifies any effects is to be examined. The issue is whether partial denervation leads to alterations in characteristics of remaining or regenerated afferent neurons supplying the urinary bladder so, that they become excited by autonomic activity and give rise to the signs and symptoms of I.C. The study proposes a systematic survey of the range of characteristics of afferent fibers excited by cystometric physiological distension of the bladder in normal adult rats in order to establish a control group baseline. As part of this survey, it is planned to gather information on whether a subset of such bladder afferent units are specialized for detection of excessive distention. Effects of stimulation of autonomic efferent nerves to the bladder and of autonomic chemical mediators (norepinephrine, Sp, VIP, neuropeptide Y, cholinergics, ATP analogues) on such afferent characteristics will be examined. How partial denervation produced by injury of the hypogastric, pelvic or sympathetic nerves (under sterile surgical conditions) modifies any autonomic modulation of sense, organ characteristics will then be evaluated. Such information on sense organs of the bladder and modifications in their characteristics under circumstances simulating clinical conditions would be a novel contribution and provide important insight into a possible- sensory neuron etiology of I.C. It has the potential of opening new approaches to treatment of this syndrome and that of other visceral disorders of possible neuropathic origin.
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1994 — 1998 |
Perl, Edward R |
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. |
Recovery and Regeneration After Spinal Neuron Injury @ University of North Carolina Chapel Hill |
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1995 — 1998 |
Perl, Edward R |
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. |
Bladder Afferent Neuron Responsiveness @ University of North Carolina Chapel Hill
This new project proposes to study modifications of the responsiveness of bladder afferent neurons produced by the autonomic nervous system and the consequences of partial denervation upon these effects. The purpose is to examine the possibility that neural trauma in the pelvic region can lead to a neuropathy affecting sensory fibers. The question to be examined: does partial denervation lead to alterations in characteristics of the remaining or regenerated afferents supplying tahe urinary bladder? The study proposes a systematic survey of the range of characteristics of afferent fibers excited by distension of the bladder in order to determine whether a subset of such afferent units are specialized nociceptors. A major impetus for the study comes from the prominence of sensory symptoms in the syndrome of interstitial cystitis and the syndrome's common occurrence in persons who may have suffered traumatic injury of pelvic structures. Bladder afferent unit characteristics will be examined in rats in association with quantitative cystometrograms. Effects of stimulation of autonomic efferent nerves to the bladder and of autonomic chemical mediators (norepinephrine, SP, VIP, neuropeptide gamma, cholinergics, ATP analogues) on such afferent characteristics are to be studied. The effects of partial denervation as a consequence of injury of the hypogastric, pelvic or sympathetic nerves on the autonomic modulation of sense organ characteristics will be evaluated. Such novel information on sense organs of the bladder and modifications in their characteristics under circumstances paralleling clinical conditions should provide important insight into the etiology of interstitial cystitis and that of other possible neuropathic visceral disorders.
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2001 |
Perl, Edward R |
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. |
Encoding in Somatic Sense Organs @ University of North Carolina Chapel Hill
DESCRIPTION (Adapted from the applicant's abstract): The long term objective of this work is to understand the mechanisms of sensory transduction in mammalian somatic receptors that sense mechanical changes. Several steps are involved in this process: transmission of the mechanical signal to the sensory terminals of the primary afferent neuron, conductance changes in the terminals-leading to the receptor potential, its electrotonic spread to the site of impulse-initiation and propagation of action potentials in the sensory axon. While the impulse train in response to a mechanical stimulus, i.e. the end result of the sensory transduction, is well known, there are very few data on the several steps leading to the sensory message sent to the C.N.S. This proposal is for study of impulse-initiation in preparations of several mechanoreceptors which can be studied in isolation. Using microscopic visualization with image processing and high speed photodetectors to record rapid changes, electrical potential changes in different regions of the sensory endings will be detected by voltage- sensitive fluorescent probes. Electrical recording with micropipettes would also be used. The site, or sites of impulse initiation, as well as their subsequent propagation, will be studied in Pacinian corpuscles and in muscle spindles. Are there multiple pacemaker sites in receptors supplied by several branches of the sensory axon? Is there propagation antidromically toward the sensory terminals? If so, how does this affect the spread of the receptor potential and the consequent sensory impulse train sent to the C.N.S? This information, in an area which has been barely explored, could greatly improve our understanding of how mechanical events are sensed. This could open up new areas of inquiry of possible importance in sensory deficits.
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