1989 — 1991 |
Lee, Kevin Scott |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
The Role of Multiple Adenosine Receptors in the Cns @ Thomas Jefferson University
The use of adenosine analogs as therapeutic agents for epilepsy and stroke has attracted increasing attention in recent years. In the central nervous system, adenosine serves as a powerful neuromodulator and has been shown to act as an endogenous anticonvulsant in certain regions of the brain. Two general classes of adenosine receptors have been identified (i.e. A1 and A2) and evidence has been presented for the existence of at least one additional type of receptor. While the powerful inhibitory action of adenosine A1 receptors on neuronal activity has been well characterized over the last decade, little is known of the physiological role of non.A1 receptors in the CNS. Electrophysiological studies (see below) indicate that non.A1 sites do indeed have a significant impact on electrophysiological responses in the hippocampus. These experiments will utilize intracellular and extracellular recording techniques to define and characterize the functional role(s) of adenosine non.A1 sites in the CNS. Dr. Lee has also demonstrated that A1 receptors are distributed differentially in the hippocampus and that non.A1 sites are associated with presynaptic elements in the stratum lucidum of CA3 and with postsynaptic elements in the stratum pyramidale of CA1. These differences permit meaningful experiments examining regions enriched in non.A1 sites which are associated with known structural elements (i.e. presynaptic or postsynaptic). The first goal of this research project is to define the physiological impact of non.presynaptic sites in the CA3 region. The second goal of these studies is to verify that the observed effects are receptor mediated and to characterize the type(s) of receptor mediating the effects. The third goal is to ascertain whether activation of protein kinase C blocks non.A1 effects, as has been described for other electrophysiological actions of adenosine in the hippocampus. The experiments should provide the first direct evidence regarding the electrophysiological function of adenosine non.A1 sites in the CNS. In addition, the studies should characterize the type(s) of receptor (i.e. A2 or another) mediating non.A1 responses. The results of these studies will greatly enhance our understanding of the adenosine neuromodulatory system and will furnish critical information for the evaluation of specific therapeutic agents designed to target individual components of this system.
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0.943 |
1989 — 1991 |
Lee, Kevin S |
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. |
Post-Ischemic Hyperexcitability--Role of Adenosine @ Thomas Jefferson University
Our hypothesis is that brain dopamine D-1 and/or D-2 receptors mediate the positive reinforcing effect of sucrose on eating. We will study sham feeding of sucrose in rats chronically implanted with gastric cannulas (to eliminate post-ingestive effects) and with brain cannulas (for central drug infusions). Four experiments are proposed, the first three use a pharmacological approach, and the fourth, a neurochemical approach. In Experiment 1, the potent, selective D-1 and D-2 receptor antagonists, SCH 23390 and raclopride, respectively, will be infused unilaterally (in separate groups) into a lateral ventricle (i.c.v.). An ID50 for inhibition of sucrose sham feeding will be determined. Necessary controls include: (1) central versus peripheral locus of inhibitory action (ID50 i.c.v. vs i.p.); (2) stereospecificity of inhibition (active vs. inactive enantiomers i.c.v.), and (3) behavioral specificity (sucrose sham feeding vs. water sham drinking). In Experiment 2, the same sequence of testing described in Experiment 1 will be conducted, but the antagonists will be microninjected bilaterally into forebrain dopaminergic terminal zones. These sites have been implicated in the positive reinforceing effects of sucrose in our previous neurochemical experiments, as well as in reinforcement by foods, drugs and electrical stimulation by others. In Experiment 3, sites at which the local applications of selective D-1 and/or D-2 receptor antagonists are found to inhibit sucrose sham feeding in Experiment 2 will be further studied pharmacologically. The chronic destruction of dopaminergic terminals in these sites identified in Experiment 2 will be performed using 6-OHDA infusions bilaterally and the effects of these lesions on sham feeding of sucrose will be determined. Dopamine agonist replacement with dopamine (DA) itself or the selective D-1 (SKF) 38393) and D-2 (LY-141865) agents will be examined. In Experiment 4, we propose to quantify brain dopaminergic metabolism (DOPAC/DA) in discrete micropunched regions corresponding to those studied in Experiments 2 and 3. This will be measured after 9 min of sham feeding sucrose, using HPLC with electrochemical detection. The results of the four experiments will provide converging pharmacological, behavioral and neurochemical evidence to test the hypothesis that specific brain D-1 and/or D-2 sites mediate the positive reinforcing effect of sucrose on sham feeding.
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1 |
1992 — 1993 |
Lee, Kevin S [⬀] |
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. |
Role of Calpain in Ischemia-Induced Brain Damage @ University of Virginia Charlottesville
The identification and characterization of cellular mechanisms responsible for expressing ischemic pathology are essential for understanding the fate of vulnerable neurons and for designing rational therapeutic strategies. The studies in this proposal will characterize the role of calcium- activated proteolysis in ischemia-induced brain damage and will evaluate the therapeutic efficacy of targeting this biochemical mechanism. The calcium-activated protease, calpain, cleaves several major cytoskeletal proteins and alters the regulation of key enzyme systems in the brain. Activation of calpain in situ results in the cleavage of brain spectrin and MAP2, both prominent cytoskeletal proteins. The uncontrolled activation of calpain would thus be expected to have detrimental effects upon cellular morphology and function. Recent studies support this idea. Spectrin breakdown products (BDPs) are markedly elevated in response to manipulations which lead to neurodegenerative responses (i.e., electrolytic lesions, colchicine injections, application of excitatory amino acids). Calpain is therefore in a position to provide a link between transient ischemia and cell death because: 1) it is activated by an appropriate signal (elevated intracellular calcium), 2) it produces appropriate effects (breakdown of cytoskeleton) and, 3) it is known to be activated in conjunction with several types of neurodegenerative responses. We have recently shown that transient ischemia induces a rapid breakdown of cytoskeletal proteins in vulnerable regions of the brain and that this proteolytic response precedes overt signs of neuronal degeneration. Data are presented here indicating that treatments which inhibit calcium- activated proteolysis attenuate morphological and functional pathologies occurring in vivo and in vitro model systems of ischemia. These results provide the first evidence of the benefits (i.e. neuroprotection) that can be derived from targeting ischemia-induced proteolysis. Furthermore, these findings strongly support the hypothesis that calcium-activated proteolysis represents a critical mechanism in the process of ischemia-induced neuronal pathology. The studies proposed in this application will evaluate and extend this hypothesis by: 1) testing the correlation between ischemia-induced proteolysis and neuronal vulnerability in multiple models of CNS ischemia; 2) characterizing the calpain response to ischemia with regard to its time course, auto-activation and relationship to its endogenous inhibitor; 3) refining techniques for suppressing calpain activity and applying these techniques to investigate the timing and critical phases of calcium- activated proteolysis, and; 4) analyzing the mechanisms involved in the activation and regulation of calpain in an in vitro model system.
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1 |
1994 |
Lee, Kevin S [⬀] |
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. |
Calpain and Ischemia Induced Brain Damage @ University of Virginia Charlottesville
The identification and characterization of cellular mechanisms responsible for expressing ischemic pathology are essential for understanding the fate of vulnerable neurons and for designing rational therapeutic strategies. The studies in this proposal will characterize the role of calcium- activated proteolysis in ischemia-induced brain damage and will evaluate the therapeutic efficacy of targeting this biochemical mechanism. The calcium-activated protease, calpain, cleaves several major cytoskeletal proteins and alters the regulation of key enzyme systems in the brain. Activation of calpain in situ results in the cleavage of brain spectrin and MAP2, both prominent cytoskeletal proteins. The uncontrolled activation of calpain would thus be expected to have detrimental effects upon cellular morphology and function. Recent studies support this idea. Spectrin breakdown products (BDPs) are markedly elevated in response to manipulations which lead to neurodegenerative responses (i.e., electrolytic lesions, colchicine injections, application of excitatory amino acids). Calpain is therefore in a position to provide a link between transient ischemia and cell death because: 1) it is activated by an appropriate signal (elevated intracellular calcium), 2) it produces appropriate effects (breakdown of cytoskeleton) and, 3) it is known to be activated in conjunction with several types of neurodegenerative responses. We have recently shown that transient ischemia induces a rapid breakdown of cytoskeletal proteins in vulnerable regions of the brain and that this proteolytic response precedes overt signs of neuronal degeneration. Data are presented here indicating that treatments which inhibit calcium- activated proteolysis attenuate morphological and functional pathologies occurring in vivo and in vitro model systems of ischemia. These results provide the first evidence of the benefits (i.e. neuroprotection) that can be derived from targeting ischemia-induced proteolysis. Furthermore, these findings strongly support the hypothesis that calcium-activated proteolysis represents a critical mechanism in the process of ischemia-induced neuronal pathology. The studies proposed in this application will evaluate and extend this hypothesis by: 1) testing the correlation between ischemia-induced proteolysis and neuronal vulnerability in multiple models of CNS ischemia; 2) characterizing the calpain response to ischemia with regard to its time course, auto-activation and relationship to its endogenous inhibitor; 3) refining techniques for suppressing calpain activity and applying these techniques to investigate the timing and critical phases of calcium- activated proteolysis, and; 4) analyzing the mechanisms involved in the activation and regulation of calpain in an in vitro model system.
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1 |
1994 — 1996 |
Lee, Kevin Scott |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Cellular Organization in the Forebrain of a Novel Neurological Mutant @ University of Virginia Main Campus
A new mutation has been discovered in a strain of rats, which produces a fundamental reorganization of the forebrain. This Small Grant for Exploratory Research will establish a stable breeding colony of these mutants, and begin to characterize the cellular organization of the forebrain. It is essential to breed the new strain of rat immediately to preserve the mutation, and make it accessible for experimentation in a variety of studies. Histological analysis of the brain of these animals will identify the types of cells in the novel structure. The established colony will provide a valuable novel model system as a resource for the community. Research on this mutation has potentially very high impact across neuroscience, because such a large change in structure suggests novel tests for structure-function relationships, as well as novel tests about neural development. Its potential impact extends beyond neuroscience to developmental biology and to biopsychology as well.
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1 |
1995 — 2000 |
Lee, Kevin S [⬀] |
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 Cerebral Microvascular Control @ University of Virginia Charlottesville
DESCRIPTION (Adapted from Applicant's Abstract): Blood flow within the brain is characterized by dynamic spatial and temporal control. The constantly shifting patterns of regional neuronal activity and the high energy demands of active neurons necessitate local mechanisms capable of regulating blood flow in a rapid and precise manner. Parenchymal microvessels are the final cerebrovascular elements responsible for supplying these needs; however, the local mechanisms through which these vessels are regulated are poorly understood. The overall goal of this application is to improve our understanding of how local mechanisms within the brain parenchyma regulate microvascular function under physiological and pathophysiological circumstances. During the initial period of support for this work, we have: 1) developed and tested novel approaches for examining parenchymal microvessels within their normal cellular microenvironment, 2) identified key local mechanisms involved in the regulation of cerebral microvascular tone, and 3) begun to examine how microvascular function is disturbed during metabolic challenge such as occurs after stroke. The Specific Aims of this proposal are to: 1) characterize the roles of local neurons and glia in the regulation of parenchymal microvessels, and 2) elucidate pathophysiological mechanisms contributing to microvascular dysfunction. The proposed studies will provide insights into a fundamental form of intercellular signalling that is involved in coupling local blood flow to local neuronal activity in the brain. A clear understanding of the physiology nd pathophysiology of microvascular control will help identify novel strategies for limiting secondary ischemic injury to the brain.
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1 |
1996 — 1998 |
Lee, Kevin S [⬀] |
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. |
Forebrain Organization @ University of Virginia Charlottesville
DESCRIPTION (Investigator's Abstract): The applicant describes the discovery of a new strain of rats that has an unusual, inherited forebrain abnormality. The behavior and external appearance of the affected animals are relatively normal, yet they possess an "entirely new brain region". Best described as a large cortical ectopia, the new structure is located below the neocortical mantle and gives the gross appearance of a 'double-cortex'. The mutant region is bilateral and extends for nearly the entire rostral-caudal extent of the cortical mantle. The existence of this rat strain is exciting for two overlapping reasons. The first is that it offers the opportunity to test a variety of theories about the relationship between structure and function in the cortex and about the ground rules of its developmental program. The second is that the anomaly observed bears a striking resemblance to a human condition known as double cortex. The applicant proposes to study this newly described abnormality in several ways. First, the applicant will perform a descriptive analysis of the types, positions and orientations of neurons in the anomalous region of adult mutant animals, as well as any effects on composition or organization of the "normal" cortex overlying the defect. Second, the applicant proposes to describe the development of the ectopia, by performing a longitudinal study at several developomental ages (during corticogenesis). These studies will be enhanced by the determination of the "birthdays" of the constituent neurons of the ectopia and the overlying normal cortex using BrdU incorporation into pups after injection of the pregnant dams at various embryonic and early postnatal ages followed by sacrifice at "adult" ages (P30 - 40). The ventricular source of the ectopic neurons and the course of their migration will be studied using short survival BrdU injections. Two to 48 hours after BrdU administration to a pregnant dam, her pups will be taken and the location of the labeled cells assessed. Third, connectivity within the ectopia and between the ectopia and other cortical and subcortical areas will be determined. Afferents to the affected region will be determined by injections of Fluoro ruby into one of three rostro/caudal sites within the anomalous region or the overlying cortex. The focus of analysis will be on the thalamic nuclei whose nuclei are associated with the overlying cortex. Efferents from the ectopia will be determined using the anterograde tracer PHA-lectin. Both of these results will be compared with similar injections from the overlying normal forebrain. The result should be a comprehensive description of the anatomy and development of this remarkable genetic anomaly.
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1 |
1997 — 2017 |
Lee, Kevin Scott |
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. |
Predoctoral Training in Neuroscience
DESCRIPTION (provided by applicant): This is a competitive renewal application for T32 support for early graduate training in the neurosciences at the University of Virginia. The Neuroscience Graduate Program (NGP) at the University of Virginia is an interdepartmental program that offers an interdisciplinary course of study leading to the Ph.D. in Neuroscience. The Program brings together 64 faculty members from 13 departments in the School of Medicine and College of Arts and Sciences to provide a comprehensive and unified program for graduate study. The overall mission of the neuroscience training program is to train Ph.D. candidates to become outstanding biomedical scientists in order to contribute to a diverse research workforce. The training grant fills a critical niche by supporting trainees in the neurosciences primarily during their second year of training. It is the only training grant at our institution that is dedicated to early-stage neuroscience graduate training. The disciplines and expertise represented range from molecular and cellular to behavioral and clinical. The breadth and depth of our faculty provide a training environment that is both unique and innovative. After building a foundation of shared knowledge and competencies for all trainees, the program embraces a trainee-specific program that is built around an Independent Development Plan (IDP). The IDP allows each trainee to craft and optimize his/her training and career trajectory together with interactive faculty advisory committees. Students are exposed to topics of human health from the earliest stages of the program in systems and disease-based courses. Careful monitoring of each trainee is provided by multiple oversight committees. Moreover, feedback mechanisms between all members of the program afford an efficient means for ongoing improvement of the program. This NIGMS-supported program has been quite successful during its past period of support producing graduates that have embraced all aspects of the modern biomedical workforce. The trainees leave the program prepared for the challenges of the current workforce and have excelled in their individual careers.
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1 |
2000 — 2003 |
Lee, Kevin S [⬀] |
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. |
Forebrain Organization in a Novel Rat @ University of Virginia Charlottesville
DESCRIPTION: (Verbatim from the Applicant's Abstract) Malformations of the cerebral cortex are present in over 1 percent of the general human population and at least 20 - 40 percent of intractable epileptics. Increasing evidence implicates misplaced cortical neurons (cortical heterotopia) in the etiology of many of the early-onset epilepsies and some forms of mental retardation. The lack of appropriate animal models for studying the natural development of human-like heterotopia associated with epilepsy represents a major impediment to understanding: 1) the roles of cortical heterotopia in epilepsy, and 2) the developmental mechanisms responsible for generating cortical heterotopia. During the initial period of support for this project, we identified and have begun to characterize a novel mutant rat (tish) that exhibits human-like cortical heterotopia. Interestingly, some tish rats display spontaneous recurrent seizures that persist over a considerable part of their life span. The tish rat thus represents a unique animal for investigating the structural, functional, and developmental aspects of a seizure prone brain with band heterotopia. The present application will focus on disturbances in cortical inhibitory systems in the tish rat with the goal of identifying mechanisms that predispose, trigger and/or maintain seizures in a brain with band heterotopia. Preliminary results indicate that fundamental disturbances in the structure and function of GABAergic systems are present in tish rats. These modifications are in a position to predispose the tish cortex to seizure activity. Other preliminary findings indicate that errors in cellular proliferation and migration play key roles in the development of band heterotopia, and these events could selectively disturb specific populations of interneurons. The studies proposed here will expand our effors to understand mechanisms of epilepsy and developmnet in a cortex with band heterotopia. The following specific aims will be addressed: 1) Identify disturbances in GABAergic interneurons in a brain with band heterotopia and define the effects of spontaineous recurrent seizures on these interneurons, 2) Elucidate developmental events contributing to the misplacement of interneurons in band heterotopia, by comparing the roles of misplaced cellular proliferation and disordered neuronal migration, and 3) Characterize inhibitory function in identified classes of projection neruons located at heterotopic versus normotopic positions in the tish cortex, and define the effects of spontaneous recurrent seizures on the functionnal properties of neurons. The proposed studies will provide fundamental insights into the structure, function and development of a seizure-prone brain with band heterotopia.
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1 |
2001 — 2003 |
Lee, Kevin S [⬀] |
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. |
Delayed Tolerance After Hypothermic Preconditioning @ University of Virginia Charlottesville
DESCRIPTION (Adapted from applicant's abstract): Ischemic injury is a common complication in a wide range of surgical procedures. Hypothermia administered during and/or after an ischemic event has proven to be clinically beneficial, and its effects rival or exceed those of other therapeutic strategies. This application describes a novel therapeutic strategy in which brief hypothermic preconditioning is used to induce a delayed form of ischemic tolerance that persists for a few days. Evidence is presented demonstrating that hypothermic preconditioning substantially reduces cerebral infarction elicited by transient focal ischemia, that this tolerance phenomenon is protein synthesis dependent and that it occurs in cells located in the brain parenchyma. The proposed work will characterize therapeutic, cellular and molecular features of hypothermia-induced tolerance by addressing the following specific issues: 1) What are the optimal hypothermic conditions for inducing tolerance? 2) Can hypothermia-induced tolerance complement the protective effects of intraischemic hypothermia? 3) Which cell types contribute to hypothermia-induced tolerance? 4) a. What are the candidate genes for mediating tolerance? b. What cell types express the candidate genes? c. What role do these genes play in ischemic neuroprotection? The ultimate goal of this project is to develop a new therapeutic strategy wherein a simple preconditioning treatment, administered well before surgery, can be used to limit subsequent ischemic injury. A parallel goal is to identify cellular sites and molecular mechanisms responsible for tissue tolerance. In as much as hypothermia is already used safely during human surgery, it is plausible that this new strategy could be implemented rapidly in the clinical setting. Hypothermic preconditioning could provide a low risk approach for improving surgical outcome after virtually any form of invasive surgery, including high-risk neurological and cardiovascular procedures. Moreover, because of the relatively benign nature of hypothermic preconditioning, it will also be possible to refine the search for salient cellular and molecular events responsible for neural tolerance. This approach will ultimately facilitate the development of novel gene-based therapies for limiting ischemic injury.
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1 |
2003 — 2004 |
Lee, Kevin Scott |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Cns Plasticity of Human Adipo-Derived Multipotent Cells @ University of Virginia Charlottesville
DESCRIPTION (provided by applicant): Stem cells and regenerative cell therapies hold great promise for treating a variety of disorders; however, an optimal cell source for translating this promise into the clinical realm remains to be determined. The use of embryonic stem cells is fraught with ethical and political controversy, and these cells present several practical issues, including adequacy of supply and non-autologous tissue responses. Adult stem cells offer a less controversial, and potentially autologous, solution; but their utility may be restricted by a limited range of developmental plasticity and an inadequacy of supply. An ideal source of cells would be abundant, expendable, replenishable, autologous, and should be easy and safe to harvest. The cells should possess considerable growth capacity, developmental plasticity, and ideally would be free of ethical and political constraints. Recently, we have demonstrated the existence of multipotent cells within human subcutaneous adipose tissue. These cells have the capacity for extensive growth, renewal, and can differentiate in vitro along ectodermally and mesodermally derived lineages. Moreover, adipose tissue represents an abundant, autologous source of cells, which can be easily and safely harvested. The studies proposed in this R21 application will investigate the plasticity of adult human adipo-derived cells (hADCs) in the rat central nervous system, hADCs are capable of differentiating into cells with neural phenotypes in vitro. Preliminary findings indicate that hADCs survive injection into the brain, migrate long distances in naive and injured (post-ischemic) brains, exhibit targeted migration to regions of injury, and survive for at least 10 weeks in vivo (the longest period tested to date). The central hypothesis of this application is that hADCs can engraft and migrate in the central nervous system, exhibit targeted migration to areas of cerebral injury, differentiate into neural cell types, and exhibit long-term survival. This hypothesis will be evaluated in the context of two specific aims. Aim 1 will identify the phenotypic and positional fates of hADCs implanted into the CNS of naive (i.e. uninjured) rats. Aim 2 will identify the phenotypic and positional fates of hADCs implanted into rat CNS after injurious transient ischemia. The results of these studies will provide the first evidence of hADC plasticity in the brain and could form the foundation for future cell-based therapies in the CNS.
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1 |
2006 — 2008 |
Lee, Kevin Scott |
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. |
Neurological Impact of Cardiopulmonary Bypass Surgery @ University of Virginia Charlottesville
[unreadable] DESCRIPTION (provided by applicant): The long-term neurological impact of cardio-pulmonary bypass (CPB) surgery can be profound. Recent studies indicate that significant cognitive decline is observed in 42% of CPB-patients when assessed five years after the procedure. This is a substantial biomedical problem because over 500,000 cardiac bypass procedures are performed each year in the United States. The underlying causes of CPB-induced cognitive decline are controversial and not well understood. The overall goal of this application is to characterize mechanisms of CPB-related injury and to evaluate a therapeutic strategy for treating long-term cognitive deficits after CPB. Our preliminary findings indicate that performance on a complex cognitive task is impaired for at least 5-6 months in a rat model of CPB. Studies under Aim #1 will characterize the behavioral impact of CPB in this replicable animal model, and will establish benchmarks for assessing long-term cognitive dysfunction after CPB. Aim #2 will examine three cellular mechanisms proposed to underlie CPB-induced injury: neuroinflammation, suppressed adult neurogenesis, and selective neuronal loss. Preliminary data indicate that sustained, localized neuroinflammation occurs in the hippocampus for at least 6 months after CPB. The preliminary findings also indicate that a substantial decrease in adult neurogenesis occurs in the area of neuroinflammation. These findings, which will be confirmed and extended under Aim #2, spur the hypothesis that sustained neuroinflammation in the hippocampus suppresses adult neurogenesis, which in turn produces long-term cognitive impairment. Aim #3 will test this concept by evaluating the protective effects of anti-inflammatory therapy on the neurogenetic and cognitive consequences of CPB. The benchmarks for behavioral impairment, established under Aim #1, will be used as a measure of cognitive function in these studies. It is hypothesized that blocking the inflammatory response to CPB will attenuate the suppression of neurogenesis and improve cognitive outcome. Together, the proposed studies will: 1) establish a means for assessing long-term cognitive deficits in a rodent recovery model of CPB, 2) characterize fundamental cellular mechanisms that underlie the deleterious effects of CPB, and 3) evaluate a specific therapeutic strategy for blocking and/or reversing cognitive decline associated with CPB. The results will expand our fundamental understanding of the mechanisms underlying CPB-related injury and will assess a rational candidate therapy for limiting cognitive decline after CPB. [unreadable] [unreadable] [unreadable]
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1 |
2008 — 2010 |
Lee, Kevin Scott |
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. |
Utility of a Novel Carotenoid For Treating Stroke
DESCRIPTION (provided by applicant): Ischemic stroke is a highly heterogeneous clinical condition resulting from an obstruction in cerebral blood flow due to thrombotic and/or embolic vascular occlusion. A key priority in the treatment of any such disturbance is to rapidly re-establish the supply of essential metabolic substrates to the affected neural tissue. This is the rationale behind fibrinolytic (clot-lysis) therapy, which facilitates the recanalization of occluded vessels, thus improving neurological outcome. It is currently the only FDA-approved drug-based therapy for the treatment of acute ischemic stroke;however, its utility is dramatically constrained by a relatively brief window of therapeutic opportunity, partial or incomplete recanalization of occluded vessels, slow recanalization of vessels, and the potential to exacerbate injury in hemorrhagic strokes. An alternative, yet complementary, approach to reestablishing metabolic competency is to facilitate the delivery of essential metabolites to the ischemic tissue. This proposal will define and characterize the utility of a therapeutic approach, termed "metabolic reflow", in which the delivery of metabolic substrates is enhanced to protect ischemic tissue. Trans-sodium crocetinate (TSC) is a novel carotenoid compound that increases the diffusivity in plasma of small molecules, including oxygen and glucose. This compound has been shown to improve oxygen delivery to a variety of tissues, including the brain parenchyma. Our preliminary studies provide the first evidence that TSC enhances oxygenation of ischemic brain tissue, exerts a potent and highly significant protective effect against cerebral injury in experimental models of both temporary and permanent ischemia, and is protective even when administered on a delayed basis. The central goal of this application is to define the protective effects of TSC in the context of ischemic stroke. The studies will examine the hypothesis that metabolic reflow is the mechanism underlying cerebral protection by TSC. The studies will identify the therapeutic window for TSC treatment, determine its optimal therapeutic dosage range, establish whether TSC is capable of extending the therapeutic window for reperfusion (clot-lysis) therapy, and define the influence of TSC on hemorrhagic stroke. Together these studies will provide key evidence for defining the mechanism(s) and utility of TSC- induced cerebral protection as a novel therapeutic candidate for early intervention in stroke. PUBLIC HEALTH RELEVANCE: This research project will study the efficacy of a new candidate therapy for treating stroke. Stroke is the third most common cause of death and the number one cause of disability in the United States. A primary cause of injury in stroke is a reduction in blood flow to the brain. This results in a loss of metabolic supply (i.e. loss of oxygen and glucose supply) to the nerve cells and ultimately leads to their death. The new candidate therapy, termed metabolic reflow will use a drug called trans-sodium crocetinate to reinstate the metabolic supply to the brain and protect against the loss of nerve cells. The overall goal of the studies is to test whether this novel therapeutic approach is effective in protecting the brain during stroke.
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1 |
2018 — 2021 |
Lee, Kevin Scott |
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. |
Precise, Non-Invasive, Axon-Sparing Surgery For the Treatment of Drug Resistant Epilepsy
Project Summary: Drug resistant epilepsy (DRE) remains a difficult biomedical challenge, affecting approximately one-third of newly-treated cases of epilepsy. Individuals impacted by DRE endure a poor quality of life, and can face life-threatening complications. Surgical removal of epileptogenic tissue can dramatically reduce seizures and improve quality of life. However, epilepsy surgery can be highly invasive, may produce damage that is not restricted to the target tissue, and is not feasible in certain critical areas of the brain. Also, surgical damage that is not conformal to its target and affects neighboring, eloquent tissue can produce long- term functional deficits. Finally, incomplete resection or ablation of target tissue can result in poor seizure management. The purpose of this proposal is to develop and test a non-invasive, targeted, conformal surgical strategy that will optimize seizure control, expand the types of epilepsies amenable to surgical intervention, and, ultimately, improve the quality of life of patients with DRE. This project will utilize Magnetic Resonance- guided, low-intensity Focused Ultrasound (MRg-FUS) to focally and reversibly open the blood brain barrier (BBB) in a targeted manner without producing a thermal lesion. Transient opening of the BBB allows timed delivery of an otherwise BBB-impermeable neurotoxin to the brain parenchyma in order to produce a focal, axon-sparing lesion of targeted neurons. The neurotoxin Quinolinic Acid (QA) is well tolerated when administered systemically at high dosages, exhibits little or no permeability through the intact BBB, is relatively unaffected by glutamatergic uptake systems in the brain parenchyma, and is capable of producing axon- sparing lesions. We present here the first evidence that systemically-administered QA combined with MRgFUS produces focal neuronal damage, while sparing axons in precisely targeted regions of the brain. Moreover, this approach affords the opportunity to treat targets that would be difficult, if not impossible, to treat using currently-available surgical techniques. Finally, these outcomes can be achieved while simultaneously limiting the risks of collateral damage, surgical side effects, and long-term neurological deficits. The current project will develop and test this novel approach for limiting seizures using a model of limbic epilepsy. The guiding hypothesis is that targeted disconnection of dysfunctional brain circuitry can be achieved in a precise, conformal, and non-invasive manner, and that this strategy can be implemented to control seizures and improve neurological outcomes. This approach provides distinct advantages over current surgical modalities as it will restrict the extent of tissue damage, allow treatment of regions that are otherwise inaccessible, reduce peri-surgical complications, mitigate against long-term functional deficits, and do all of this in a non-invasive manner. Notably, this strategy could prove useful for treating a variety of neurological disorders in which disturbances in connectivity play a role.
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