1985 — 1986 |
Hulsebosch, Claire E |
R23Activity Code Description: Undocumented code - click on the grant title for more information. |
Axonal Regeneration and Nerve Growth Factor @ University of Texas Medical Br Galveston
This proposal is designed to begin to study the parameters of axonal sprouting induced by Nerve Growth Factor (NGF) and by spinal cord denervation. The methods will be ultrastructural quantitation of the myelinated and unmyelinated axons of appropriate nerves and roots, light microscopic quantitation of neurons and autoradiography. Preliminary data indicate that endogenous NGF is implicated in the sprouting of central processes of dorsal root ganglion neurons after spinal cord denervation at birth. Other preliminary evidence indicates that a small population of dorsal root ganglion neurons are labeled with radiolabeled-NGF after spinal cord injury suggesting that a specific group of neurons may sequester NGF after injury. Consequently the obectives of this proposal are: 1) to quantify the effects of nerve growth factor in the uninjured mammal by examination of specific neural pathways in rats treated with NGF or the antibody to NGF, 2) to quantify the involvements of NGF in the sprouting response of dorsal root ganglion neurons after spinal denervation by administering NGF or its antibody to rats with spinal damage, 3) to investigate the dorsal root ganglion neuron population that binds radiolabeled NGF after spinal cord denervation. Given that the amount of sprouting may be related to functional recovery and that endogenous NGF would seem to be implicated in the response to spinal cord denervation, the establishment of these parameters may lead to futher studies designed to test the clinical applicability of these manipulations.
|
0.984 |
1988 — 1995 |
Hulsebosch, Claire E |
K04Activity Code Description: Undocumented code - click on the grant title for more information. 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 Sprouting in the Spinal Cord @ University of Texas Medical Br Galveston
Previous work in my laboratory demonstrated an increase in the number of fibers of primary sensory afferents in the dorsal root after unilateral spinal cord denervation. This increase is primarily in the unmyelinated fiber population and is interpreted as sprouting. In an effort to manipulate this phenomenon, the protein Nerve Growth Factor NGF) and antibodies to NGF (Anti-NGF) were given to denervated and normal neonatal rats. Work to date indicates that NGF had little effect on neuron or axon populations but after anti-NGF treatment, a population of small neurons in the dorsal root ganglion dies and the remaining neurons emit more processes than before. It is the goal of the present research proposal to pursue the extent and molecular mechanisms of the neural reorganization caused by anti-NGF in the following specific aims: 1) To determine composition and origin of sprouting fibers in the spinal cord. 2) To determine molecular markers for the sprouted presynaptic endings and postsynaptic structures in the dorsal horn. 3) To determine which cell populations synthesize NGF, have receptors for NGF, and accumulate and bind NGF in the central and peripheral nervous systems. Techniques include ultrastructural stereology, immunocytochemistry, autoradiography and in situ hybridization. This information will contribute to the understanding of molecular mechanisms underlying the selective death and sprouting of neuronal populations in response to exogenous factors. This knowledge will contribute to the use of exogenous drugs toward manipulations of specific neuronal populations in clinical situations.
|
0.984 |
1996 — 2000 |
Hulsebosch, Claire E |
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. |
Chronic Central Pain After Spinal Cord Injury @ University of Texas Medical Br Galveston
It is the long-term objective of this laboratory to improve functional outcome after spinal cord injury (SCI). One important issue is the chronic pain sensations that the majority of patients with SCI experience. This project focuses on the development of a mammalian model of chronic central pain that is reproducible and has both spontaneous and evoked pain components, an important contribution which will allow an investigation of mechanisms and possible therapeutic interventions. There are four hypotheses to be tested: 1. Spinal cord injury produces chronic pain which can be measured as alterations in evoked behaviors. 2. Excitatory amino acids (EAA) and peptides play important roles in the alterations of evoked somatosensory behavior observed after spinal cord hemisection. 3. EAAs and peptides play an important role in central sensitization of dorsal horn neurons in nociceptive pathways in this SCI model. 4. Spinal cord injury produces chronic pain which can be measured as alterations in spontaneous, non-evoked behavior. Methods include behavioral tests, electrophysiological recordings, microdialysis and behavioral outcome of pharmacological intervention. These data will contribute toward understanding the symptomology and behavioral changes characteristic of partially spinalized patients.
|
0.984 |
2001 — 2005 |
Hulsebosch, Claire E |
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. |
Chronic Central Pain in Spinal Cord Injury @ University of Texas Medical Br Galveston
The research program is focused on mechanisms of excitotoxicity- induced chronic central pain (CCP) after SCI. The rodent contusion model of SCI will be used for assessing CCP and to explore the contributions of excitatory amino acid (EAA)-mediated mechanisms that lead to cell death after SCI. We hypothesize that damage caused by the elevated levels of EAA is causally related to the development of chronic pain as well as other dysfunctional states after SCI. The three projects will test molecular, biochemical and functional outcomes of interrupting EAA release of transport mechanisms and inhibiting EAA receptor- mediated processes, including apoptosis, in a combination of approaches. Project 1 will assess behavioral outcome and AA receptor and transporter distribution and density following blockage of EAA mediated processes and interventions of apoptotic pathways after SCI. Project 2 will measure EAA concentrations acutely after contusion injury and examine the role after EAA release, receptors and transporters play in neuronal loss after SCI. Project 3 will measure the expression levels of early genes (p50, p65, p49) activated by glutamate receptor-mediated mechanisms and the resulting downstream changes in expression of genes (Bcl-2 gene family) that influence neural cell survival after SCI. There are three cores: an administrative core, an animal core and a morphology core. The results for these studies will guide the development of strategic interventions to improve functional outcome after SCI.
|
0.984 |
2001 — 2005 |
Hulsebosch, Claire E |
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. |
Role of Lif and Ngf in Inflammation and Chronic Pain @ University of Texas Medical Br Galveston
This project addresses the regulation of neuropeptide expression in chronic pain that appears following spinal cord injury. Such pain is often a severe affliction for the victim. A model established in our laboratories to investigate the pain that follows spinal cord injury will be utilized. In this model, pain-like behaviors that appear following hemisection of the rt spinal cord are assessed. The model reproduces the salient features of post spinal cord injury in humans. Our central hypothesis is that expression of the cytokine leukemia inhibitor factor (LIF) counteracts the development of chronic pain following spinal cord injury by increasing the expression of the neuropeptide galanin and decreasing the expression of the peptides nerve growth factor (NGF), substance and calcitonin gene related peptide. This hypothesis includes a sub-hypothesis that LIF acts on the synthesis of the latter peptides by reducing the biosynthesis of NGF. Existing evidence suggests that increased LIF reduces manifestations of pain in peripheral neuropathy and inflammation models by altering the production of neuropeptide inter cellular messengers. However, since this is unaddressed for the pain that develops following spinal cord injury, the biosynthesis of all of the above peptides and their effects on pain-like behaviors following spinal cord injury will be characterized. Time courses of effects of injury on peptide biosynthesis will be determined by analyzing peptides in tissue from the area of injury by ELISA or RIA assays and by immunocytochemistry. Roles of these peptides in pain expression will be tested by blocking their actions during times of increased expression or adding them when their expression is decreased, together with measuring pain-like behaviors in the experimental animals. The actions of LIF or NGF will be manipulated so as to increase peptide synthesis and then the action of that peptide will be blocked to establish whether modulation of peptide biosynthesis by LIF and NGF influences pain-like behaviors. Effects of LIF of inflammation and associated pain will also be characterized. Insights from this work will aid in developing treatments for pain that appears following spinal cord injury, currently a clinically intractable problem.
|
0.984 |
2008 — 2012 |
Hulsebosch, Claire E |
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. |
Imaging Core @ University of Texas Medical Br Galveston
Core C is the Imaging Core. The purpose of this core is to provide access and training for the two Image Analysis Systems (Nikon E800 and E1000 fluorescent scopes with DIG optics and imaging software) and the three Confocal Laser Scanning Microscopes (FluoView, BioRad and Zeiss LSM510META Confocal Scanning Systems). The equipment will be used for density measures, cell counting, photodocumentation, production of digitized images and other needs as the projects require. There are three core locations: one on the second floor, one on the tenth floor of the Medical Research Building and the Zeiss LSM510META is located on the fourth floor of the contiguous Basic Science Building. For this program, all three are managed by a committee that consists of the Core Directors and Pi's on the program project and allows access to equipment that would otherwise be too expensive for each laboratory to own and maintain. Evidence of use by each project is described and it is clearly important for the production of data in all three projects. Personnel include a Core Director (0.60 cal. hrs.), a Core Co-Director (salary on ROS Analytical Core) and a research scientist (6.0 cal. hrs.). Note that the function of this Core compliments the Histopathology section of the ROS Analytical Core (Core B).
|
0.984 |
2008 — 2012 |
Hulsebosch, Claire E |
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. |
Role of Ros in Sensitization After Spinal Cord Injury @ University of Texas Medical Br Galveston
An emerging concept in mechanisms that lead to neuropathic pain is elevated intracellular levels of reactive oxygen species (ROS) in peripheral and central sensitization. The overall hypothesis of the PPG is that ROS act as key signaling molecules in concert with other signaling pathways involved in sensitization. In that context, the present proposal examines spinal cord injury (SCI) induced chronic central neuropathic pain (CNP). This is a major public health problem;consequently, an understanding of the mechanisms of CNP will lead to opportunities for treatment of this terrible condition. We will use the rodent spinal cord contusion model because this model best approximates human SCI. CNP in this model includes above level (C7/C8, forelimb innervation), at level (T8, trunk innervation) and below level (L4/L5, hindlimb innervation) pain-like behaviors seen clinically. CNP is thought to be generated in these different clinically relevant regions by different mechanisms. In this project, we will test the hypothesis that generation of ROS after SCI contributes to central neuropathic pain by both peripheral and central sensitization via activated calcium/calmodulin kinase II (pCamKII) pathways. We will test the following specific aims: 1) Determine the time course of development of CNP behavior in the rodent contusion model. 2) Determine the time course of development of central and peripheral sensitization above level, at level and below level after SCI. 3) Test the sites of action of ROS inhibitors and the effects of these substances separately at those sites on CNP behaviors early and in chronic SC and on pCamKII expression levels. 4) Determine the effect of ROS inhibition (by the most effective agent and route determined by behavioral outcomes in Specific Aim 3) on central and peripheral sensitization early and in chronic SCI and on ROS expression levels. Outcome measures include behavior, electrophysiology, protein expression and immunocytochemistry. Our results will expand on Project 1 (ROS in peripheral sensitization after inflammation), Project 3 (role of ROS in C-fiber driven central sensitization) and Project 4 (role of ROS in amygdala and central sensitization) to give insight into mechanisms that provide common bases for development and maintenance of CNP and indicate therapeutically useful strategies for intervention in neuropathic and inflammatory pain syndromes.
|
0.984 |