1988 |
Mcintosh, Tracy K. |
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. |
Endorphins and Catechholamines in Shock and Trauma @ University of Connecticut Sch of Med/Dnt
The objectives of the studies outlined are to establish the role of specific endogenous opioid peptides in the pathophysiology of hemorrhagic shock and to facilitate the development of improved therapeutic approaches to shock and trauma. Preliminary studies from this laboratory have demonstrated that endogenous opioids, including the dynorphin/kappa-receptor system, may be involved in the regulation of cardiovascular function during shock. We propose to use newly available technology to elucidate the mechanism by which specific opioid systems mediate cardiovascular dysfunction during hemorrhagic shock. In the proposed studies, the role of specific opioid peptides (particularly dynorphin) and opioid receptors will be examined with regard to the pathophysiology of acute hemorrhagic shock in the rat. Plasma concentrations of opioid peptides and catecholamines will be determined before and after the induction of shock. Changes in brain opiate receptor binding sites and brain opiate immunoreactivity will be measured in specific regions associated with cardiovascular regulation from control and injured animals in order to examine the effects of shock on regional peptide concentrations and opioid receptor distribution. "Micropunch" techniques will also be employed to examine opioid immunoreactivity and receptor changes in important central cardiovascular nuclei which may mediate the compensatory or decompensatory response to shock. Post-shock changes in plasma opioid concentration, central nervous system opiate immunoreactivity and receptor distribution will be related to alterations in mean arterial pressure, cardiac output/stroke volume and regional blood flow to specific peripheral vascular beds. To further determine whether dynorphin and/or the kappa- opiate receptor contribute to the sequelae of shock, we will evaluate whether centrally administered kappa-opioid receptor agonists exacerbate the physiological response to shock. Finally, the therapeutic efficacy of two novel opioid antagonists nalmefine and WIN44,441-3 (which have increased activity at kappa sites) will be evaluated and compared to that of naloxone in hemorrhagic shock. Taken together, these proposed studies will enhance our understanding of the pathophysiological mechanisms that underlie hypotension and low-flow states that accompany shock and trauma and may result in the development of new and more effective therapeutic approaches to the treatment of hemorrhagic shock.
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0.901 |
1989 — 1992 |
Mcintosh, Tracy K. |
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. R55Activity Code Description: Undocumented code - click on the grant title for more information. |
Role of Magnesium in the Pathophysiology of Brain Injury @ University of Pennsylvania
This is a Shannon Award providing partial support for research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. Further scientific data for the CRISP System are unavailable at this time.
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0.907 |
1991 — 1994 |
Mcintosh, Tracy K. |
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. |
Endorphins in Shock and Trauma @ University of Pennsylvania
The objectives of the studies outlined in this renewal application are 1) to establish the role of specific endogenous opioid peptides in the pathophysiology of hemorrhagic shock, 2) to further elucidate the role of the dynorphin and kappa opiate receptor system in mediating the sequelae of hemorrhagic shock, and 3) to facilitate the development of improved therapeutic approaches to shock. Preliminary studies from this laboratory have demonstrated that endogenous opioids, including the dynorphin/k- receptor system, may be involved in the regulation of cardiovascular function during shock. We propose to continue these promising studies using newly available technology to elucidate the mechanism by which specific opioid systems (particularly dynorphin) may mediate cardiovascular and metabolic dysfunction during hemorrhagic shock in the rat. Alterations in gene expression of prodynorphin, preproenkephalin and proopiomelanocortin messenger RNA (mRNA) will be measured (blot hybridization) in discrete brain regions before and after hemorrhagic shock. Changes in regional brain opiate receptor binding (including kappa isoreceptors) will be measured in brain areas associated with cardiovascular regulation in order to examine the effects of shock on opioid receptor regulation. "Micropunch" techniques will also be employed to examine receptor changes in important central cardiovascular nuclei which may mediate the compensatory or decompensatory response to shock. Post-shock changes in gene expression of opioid precursors and receptor distribution will be related to alterations in mean arterial pressure, cardiac output/stroke volume (Cardiomax computer), regional blood flow to both brain and specific peripheral vascular beds (radiolabeled microspheres) and brain metabolism (Phosphorus Nuclear Magnetic Resonance Spectroscopy -31P NMR). We will also evaluate whether centrally administered k-opioid receptor agonists, microinjected into discrete brain cardioregulatory nuclei, exacerbate cardiovascular or brain metabolic dysfunction during shock. Finally, the therapeutic efficacy of two novel opioid antagonists, nalmefene and nor-binaltorphimine (which have increased activity at k sites), will be evaluated and compared to that of naloxone. Taken together, these proposed studies will enhance our understanding of the pathophysiological mechanisms that underlie hypotension and low-flow states that accompany shock and trauma and may result in the development of new and more effective therapeutic approaches to the treatment of hemorrhagic shock.
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0.907 |
1994 — 1998 |
Mcintosh, Tracy K. |
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. P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Head Injury Clinical Research Center @ University of Pennsylvania
This grant application seeks continued funding for the Head Injury Research Center at the University of Pennsylvania, a Center now in its 23rd year of existence. During that time, the research has become focused on TRAUMATIC AXONAL DAMAGE (TAD), an important focus of dysfunction in human brain injury, and, thus, TAD is the overall theme of the Center. TAD occurs in various forms in well over half of all fatal injuries examined pathologically and in a pure form, as diffuse axonal injury (DAI), in one-third of severely brain injured humans. To understand the pathophysiology of TAD better, this application proposes the use of state-of-the-art neuroimaging, spectroscopy, electron microscopy, immunohistochemical and molecular biologic methods in a coordinated research effort involving five projects. The first two projects utilize magnetic resonance transfer imaging (MTI) and spectroscopy (MRS) to determine non-invasively longitudinal changes in structure and in-vivo biochemistry of traumatic white matter abnormalities in experimental DAI and humans, respectively, and will combine these into methods to diagnose TAD clinically. A third project characterizes changes in expression of immediate early genes (IEG), stress proteins, target genes of the IEGs and neurotransmitters in models of TAD in order to determine the influence of genomic changes on responses to injury. A fourth project uses experimental models of TAD to determine efficacy of novel neuroprotective compounds targeted at receptor or cytoskeletal dysfunction in mitigating TAD. Two essential core activities support the Projects. Core A provides administrative activities, biostatistical support, patient database maintenance and evaluation of new outcome tools. Core B provides bioengineering support, designs improved models with higher fidelity in replicating human brain injury, and quantifies the relationships between experimental models and human injuries. Theses studies will further our understanding of the pathophysiology of brain injury and will lead to the development of novel and improved therapies for the treatment of brain injured patients.
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0.907 |
1994 — 1998 |
Mcintosh, Tracy K. |
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. |
Magnesium and the Pathophysiology of Brain Injury @ University of Pennsylvania
Recent work from our laboratory has suggested that changes in the magnesium ion (Mg2+) may play an important role in mediating the pathophysiological sequelae of traumatic brain injury (TBI). Magnesium is a critical ion in the brain for the regulation of cellular bioenergetics and changes in brain Mg2+ concentrations after trauma can potentially alter regional brain metabolism, cerebrovascular function and intracellular calcium flux, thereby directly affecting post-traumatic neuronal susceptibility to damage. The objects of the studies outlined in this application are to (1) characterize changes in extracellular and intracellular concentrations of Mg2+ after experimental brain injury, (2) determine whether Mg2+ deficiency alters post-traumatic outcome and whether maintenance of Mg2+ homeostasis is neuroprotective after brain injury, (3) examine the efficacy of pharmacotherapies that interact with the Mg2+ homeostasis is neuroprotective after brain injury, complex, and (4) determine whether the beneficial effects of diverse pharmacotherapies known to be effective in brain injury are associated with the recovery of tissue Mg2+ and enhanced bioenergetics status. Extracellular concentrations of Mg2+ will be characterized over time after fluid- percussion (FP) brain injury of graded severity int he rat using intracerebral microdialysis and atomic absorption spectrophotometry. Changes in intracellular Mg2+ will be assessed using phosphorus (P) nuclear magnetic resonance (NMR) spectroscopy. Post-injury changes in extracellular and intracellular Mg2+ will be related to alterations in regional cerebral blood flow (rCBF, radiolabeled microspheres/iodoantipyrine autoradiography), cerebral bioenergetics (P NMR), histopathological damage, neurologic (motor), and cognitive (Morris Water Maze) deficits. Molecular biology techniques will be employed to examine the relationship between post-traumatic alterations in brain magnesium and expression of mRNA for heat-shock protein (HSP-72) and the immediate early genes (IEG) c-fos/c-jun. In order to begin to determine the fate of the magnesium ion following trauma, we will measure magnesium concentrations in plasma and cerebrospinal fluid (CSF). We will also evaluate whether Mg2+ deficiency following dietary restriction will affect post-traumatic outcome and whether post-injury treatment with Mg2+ will improve post-traumatic cerebrovascular, metabolic, histopathologic, and behavioral function. Finally, the therapeutic efficacy of the competitive NMDA antagonist CGS19755, the AMPA/KA receptor antagonist GYKk152466, the novel presynaptic glutamate release blocker BW619C89, and the NMDA-associated glycine receptor antagonist kynurenate will be evaluated for their effects on post-traumatic rCBF, metabolism, neuronal damage, and behavioral function. A "critical window" for post-traumatic pharmacologic intervention will be assessed using the most optimal combination of pharmacotherapies. Taken together, these proposed studies will enhance our understanding of the pathophysiological mechanisms that underlie cerebrovascular, metabolic, histologic, and behavioral damage associated with TBI and result in the development of new and more effective therapeutic approaches to the treatment of brain trauma.
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0.907 |
1995 — 2003 |
Mcintosh, Tracy K. |
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. |
Central Nervous System Dysfunction in Shock and Trauma @ University of Pennsylvania
DESCRIPTION: (Adapted from the applicant's abstract) The objectives of the studies are: 1) to elucidate the molecular mechanisms underlying the role of brain dynorphin/kappa opiate receptor systems in mediating the CNS response to hypotension; 2) to characterize the temporal and regional alterations in immediate early gene, stress protein and cytokine expression in the brain and correlate such changes with gene expression for opiate peptides and with the cardiovascular and histologic response to hemorrhage; 3) to characterize the presence and regional activation of programmed cell death in the brain; and 4) to facilitate the development of improved molecular and pharmacologic therapeutic approaches to shock. Preliminary studies have documented that endogenous opiates, most notably dynorphin, appear to be involved in the central regulation of cardiovascular function during hemorrhagic shock. Molecular investigations will continue along this line with selected areas of brain dysfunction identified. The investigators will examine the therapeutic efficacy of the k-opioid receptor antagonist, nor- binaltorphimine, the calcium channel blocker, (s)-emopamil, the IL-1 receptor antagonist, IL1-RA, and the antibody to TNFa alone or in combination. The studies are to enhance current understanding of the molecular sequelae of hypotension and low flow states that accompany shock and trauma so as to foster the development of more effective pharmacologic and genetic therapeutic approaches to treating shock.
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0.907 |
1996 — 1998 |
Mcintosh, Tracy K. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Neuroprotection After Traumatic Injury @ University of Pennsylvania
Excessive increases in intracellular calcium appear to be a critical pathophysiologic event in many histopathological sequelae of traumatic brain injury. Although considerable attention has been recently given to the potential neuroprotective effects of pharmacologic antagonists of the N-methyl-D-aspartate (NMDA) receptor (Which act by reducing calcium influx into neurons via glutamate receptor-associated ion channels), it is unlikely that these agents will be singularly efficacious in all types of brain injury. Moreover, since the neurochemical cellular and molecular sequelae of TBI are diverse and varied, it is likely that some form of combined (cocktail) therapy will be optimally effective in reversing the secondary consequences of CNS trauma. Using a coordinated set of laboratory models, and our experience with pharmacologic intervention, we propose to evaluate novel pharmacologic compounds that can affect calcium-induced cell death and examine the following hypotheses: 1) that neuronal damage following axonal injury primarily involves cytoskeletal degradation and will be optimally protected by therapeutic agents that attenuate or prevent cytoskeletal injury and proteolysis (specific inhibitors of calcium-activated neutral proteases (CANPs), including the calpain inhibitor Ceph 1190 and calpastatin), 2) that the neuronal damage following isolated cortical injury involves receptor-mediated dysfunction and may therefore be more amenable to pharmacotherapies targeted at receptor systems (NMDA, non-NMDA and calcium-channel) believed to be involved in post-traumatic calcium influx (the non-NMDA antagonist GYK152466, the competitive NMDA antagonist LY233053, the presynaptic glutamate release blocker BW619C89, or novel calcium-channel/serotonin antagonist (s)-emopamil); and 3) that experimental models of mixed axonal/cortical injury, such as lateral fluid-percussion brain injury, will maximally benefit from a combination (cocktail) of both types of pharmacotherapies.
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0.907 |
2000 — 2003 |
Mcintosh, Tracy K. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Mechanisms of Cell Death After Traumatic Brain Injury @ University of Pennsylvania
Traumatic brain injury (TBI) in humans as an incredibly heterogeneous disease and the significant effort involved in developing and characterizing reproducible and clinically-relevant models of specific types of TBI has enabled the neurotrauma research community to begin to identify important and injury-specific mechanisms of cell death and dysfunction. This application revolves around the general hypotheses that selective molecular and cellular pathways are activated or initiated which are injury-specific mechanisms of cell death and are activated or initiated which are injury-specific. Through the sue of selective experimental models that closely simulate the major classes of human TBI, we can better understand and characterize the pathological sequelae of clinical head injury and explore novel mechanistic-based therapies. We have chosen to focus on several exciting areas, including (1) the relationship between TBI and the cellular events associated with Alzheimer's and other neurodegenerative disease, (2) the role of the dysfunctional cytoskeleton and calpain-mediated cytoskeletal proteolysis in post- traumatic neuronal death and damage, and (3) the activation of cell death enzymes such as MAP kinases and caspases and their role in post- traumatic cell death. We will continue to forge mechanistic links between these pathological cascades and outcome following TBI. We will also evaluate (4) the important role of secondary hypoxia/ischemia in the exacerbation of cellular injury and the association with one or more of the pathologic mechanisms studied in these Projects. Finally, we will use the accumulated molecular and cellular information to design and drive novel neuroprotective strategies to enhance recovery of function and attenuate neuronal cell death. These projects will be significantly supported by human/histopathology, biomechanics, molecular biology, and administrative cores. We believe that the understanding of the specific cellular and molecular mechanisms underlying cell death and dysfunction is critically important to the continuation of scientific progress in this field and to the development of novel therapeutic strategies targeted to treat human brain injury.
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0.907 |
2001 — 2004 |
Mcintosh, Tracy K. |
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. |
Neuroprotective Growth Factors in Traumatic Brain Injury @ University of Pennsylvania
DESCRIPTION: (Verbatim from the Applicant's Abstract) The mechanism(s) of delayed secondary injury following traumatic brain injury (TBI) may involve the alteration of specific intracellular signaling pathways involving the mitogen activated protein (MAP) kinases JNK and Erk 1/2, as well as long-term genomic changes. These pathogenic molecular events provide targets for treatment with growth factors intended to prevent or limit neurologic disability. The investigators, among others, have generated preliminary data suggesting that acute (24 hr postinjury) administration of exogenous NGF or basic fibroblast growth factor (bFGF) may be neuroprotective in experimental models of brain injury. Specific Aim 1 will assess whether administration of either NGF or bFGF in the acute post-traumatic period (beginning 24 hr postinjury) will attenuate long-term neurologic disability and neurodegenerative (apoptotic/necrotic) cell loss following experimental lateral fluid percussion (FP) brain injury in rats. The investigators will selectively infuse these growth factors directly into the injured brain over a 2-week postinjury period, and behaviorally evaluate the animals over a chronic 3-month postinjury period for neurologic motor and sensorimotor dysfunction, cognitive deficits, and regional cell death. Specific Aim 2 will evaluate the temporal and regional alterations in specific MAP kinase (JNK/Erk 1/2) signaling pathways following experimental FP brain injury, and relate the neuroprotective effects of therapy with NGF or bFGF to a reversal of the pathologic changes in JNK/Erk induced by trauma. They will use Western blotting and immunohistochemistry to support their pilot data that TBI results in activation of the pro-death kinase JNK signaling pathway and a concomitant decrease in signaling through the pro-survival Erk 1/2 pathway. The effects of NGF or bFGF therapy and cessation of 2-week therapy (i.e., growth factor withdrawal) on these trauma-induced signal transduction cascades will then be regionally and temporally evaluated. In Specific Aim 3, they will quantify the effects of NGF or bFGF therapy on trauma-induced alterations in expression profiles of genes involved in cell death/survival and long-term plasticity/remodeling of the injured CNS. The investigators will use laser capture microdissection and reverse-Northern hybridization techniques with custom-designed slot-blots to quantify expression levels of a selected panel of genes, including cell death/survival genes, cytoskeletal genes, growth-related proteins, and cytokines. Genomic changes will be confirmed at a translational level with immunohistochemistry for selected proteins. In Specific Aim 4, the investigators will selectively infuse NGF or bFGF into the injured brain over a 2-week treatment period beginning 2 weeks or 1 month postinjury and evaluate the ability of these delayed treatment paradigms to improve long-term neurological motor and cognitive function (up to 3 months postinjury) and attenuate progressive post-traumatic cell death.
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0.907 |
2003 |
Mcintosh, Tracy K. |
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. |
Brian Injury Training Grant @ University of Pennsylvania
[unreadable] DESCRIPTION (provided by applicant): The proposed program will train M.D., Ph.D. and medical student investigators in state-of-the-art techniques to investigate the molecular and cellular mechanisms underlying central nervous system (CNS) injury. The trainees will be: 1) Physicians involved in the University of Pennsylvania Neurosurgical residency-training program, 2) Ph.D. scientists with prior training in molecular biology, or 3) selected medical students who are participating in Penn's unique Clinical Neuroscience Track program. This program will provide background and training in molecular neurobiology and an introduction to CNS disorders where these new techniques can be applied. This program will be a laboratory-based research-training program that includes experience in novel molecular biology techniques in an interactive and supportive setting. The institution has an extensive didactic program in basic and clinical neurosciences, neurodegeneration, CNS injury, and molecular biology including gene therapy, which will be individually designed for each trainee in order to supplement the laboratory experience. Each trainee will design and complete an independent project providing experience in design and analysis of experiments and in the presentation and publication of results. Weekly trainee research seminars and monthly faculty/trainee mini-symposia provide constant interchange and exchange between faculty trainers and trainees. This program will be run by individual faculty trainers who are the leaders in their field at the University of Pennsylvania, representing disciplines such as CNS ischemia and trauma, neurodegenerative diseases, inheritable neurological disorders, demyelinating diseases, epilepsy, neuroanesthesiology, molecular virology, gene therapy, and molecular pharmacology. Each trainee selects one laboratory for the primary research project but will have complete access to the other trainers for advise, technical assistance, and collaboration. Each trainer has independent NIH funding and all have active and internationally-recognized research programs. Core services available within the University of Pennsylvania, Wistar Institute, Children's Seashore House, and the Institute of Human Genome Therapy include protein sequencing, oligonucleotide synthesis, transgenic knock out/ knock in technology, automated DNA sequencing, viral vector construction, and gene therapy techniques. No funding mechanism currently exists at the University of Pennsylvania to support these trainees. The funding of this Brain Injury Training Grant (BITG) application will establish a novel and important infrastructure involving a highly collaborative faculty for the purpose of training future research scientists and clinicians in the state-of-the-art techniques related to an important clinical disease. [unreadable] [unreadable]
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0.907 |