1996 — 1998 |
Hovda, David A |
P41Activity Code Description: Undocumented code - click on the grant title for more information. 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. |
Excitotoxic and Neuronal Dysfunction in Brain Injury @ University of California Los Angeles |
0.958 |
1997 |
Hovda, David A |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
15th Annual National Neurotrauma Symposium @ University of California Los Angeles
Funds are requested for partial support of the 15th annual National Neurotrauma Symposium to be held in conjunction with the Society for Neuroscience Annual Meeting in New Orleans, LA, October 24-25, 1997. This two-day symposium will feature 14 lectures focusing on six main themes covering basic and clinical scientific advances and the study of traumatic brain and spinal chord injury. In addition, speakers will be selected from submitted abstracts on the basis of scientific merit, originality and relevance to the study of neurotrauma, Moreover, approximately 175 poster presentations will be available for viewing over the two-day period. The specific aims of the 15th Annual Neurotrauma Symposium are to: 1. Provide the most current information in neurotrauma research to both basic scientists and clinicians investigating and/or treating traumatic, ischemic and related injuries to the brain and spinal cord. Session themes include: (a) Recovery of Functional Reflections of Plasticity, (b) Measures of Recovery of Function: Animal Studies, (c) Developmental Effects on Recovery of Function, (d) Effecting Recovery of Function, (3) Effecting Recovery in Human Head Injury, (f) Multi Center Preclinical Designs to Foster Clinical Trials. 2. Encourage the interest of students, residents and postdoctoral fellows in neurotrauma research. 3. Develop strategies for increasing the participation of qualified women and minorities in annual neurotrauma symposia and research. 4. Encourage established neuroscientists from other fields to become involved in neurotrauma research. Thus, through formal lectures, poster sessions and informal discussions between individuals, the overall objective of this symposium is to promote and support communication among basic and clinical scientists concerned with the study and treatment of injury to the brain and spinal cord. Importantly, the program and abstracts submitted for presentation at the National Neurotrauma Symposium will be published in the Journal of Neurotrauma prior to the conference.
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0.958 |
1998 — 2002 |
Hovda, David A |
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. |
Tbi Induced Cellular Vulnerability--Cerebral Blood Flow &Metabolism @ University of California Los Angeles |
0.958 |
1999 — 2002 |
Hovda, David A |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Excitotoxic &Neuronal Dysfunction in Brain Injury @ University of California Los Angeles
The long-term goal of this research is to build a better bridge between the tissue, cellular, and molecular levels of analysis of the frog embryo. The specific goal of this proposal is to probe the nature of molecular expression domains in the early embryo. The ability of pMRI to follow tissue movements and cell lineages in three dimensions over time in opaque specimens will be used, in conjunction with conventional molecular biology techniques, to map the lineages that contribute to a gene expression domain as well as the fates of the cells that were once within the domain. The specific hypothesis to be tested is that the gene expression domains are made up of dynamic populations of cells, requiring that cells express the marker gene as they enter a given domain, and extinguish it as they exit the domain. Towards this end, we will: (1) determine the normal lineages of cells that contribute to the frog nervous system. the axial mesoderm and the paraxial mesoderm: (2) determine the rel ationship between the early lineages and differential patterns of gene expression: (3) determine the changes in cell lineages and cell movements in perturbed embryos 1. Goal Directed Imaging: (a) provide comprehensive three-dimensional in vivo images of the developing brain in three different species (quail, mouse, and monkey) using Magnetic Resonance (MR) micro-imaging, (b) use fMRI techniques to examine how the visual field map of the owl monkey changes with increasing degree of myelination in brain of the young animal. 2. Analysis: (a) analyze the images at a number of different levels ranging from simple annotation to correlating the onset and developing organization of different structures in both space & time and to compare & contrast the avian, rodent, and mammalian systems. (b) mesh optical and MRI data of the same animal. 3. Dissemination: (a) make the images and tools for rendering & analysis available to the scientific community in a convenient format. e.g., photographs of 2D slices of the 3D data. CD-ROMs with annotated 2D and 3D images to be viewed using readily available software and software developed in-house. and an on-line database accessible via the World Wide Web where raw' as well as 'processed' data will potentially be available.
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0.958 |
2001 — 2010 |
Hovda, David A |
P41Activity Code Description: Undocumented code - click on the grant title for more information. 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. |
Loss of Developmental Plasticity After Head Injury @ University of California Los Angeles
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Children in the United States have a higher chance of being killed or disabled by a traumatic brain injury (TBI) than by any other "disease". We have discovered that developmental TBI impairs the ability of young animals to interact with and benefit from rearing in an enriched environment (EE) [4;5]. The ability to interact and experience is a critical function underlying normal maturation;however, the mechanisms of this 'experience-dependent neuroplasticity'are only beginning to be understood. Excessive activation of the N-methyl-D-aspartate receptor (NMDAR) occurs following TBI and can lead to cell dysfunction and death [6;7]. However, too little activation can impair normal development and blunt recovery from injury [8]. The NMDAR is intimately involved with a unique growth factor, brain-derived neurotrophic factor (BDNF). Increases in BDNF occur in response to specific environmental experiences, such as rearing in an EE or exercise [9;10;11], and these increases are associated with enhanced plasticity and cognition. We propose that early TBI results in a reduction of developmental potential, and that this impairment occurs via a mechanism where physiological activation of the NMDAR/BDNF system is deranged by a pathological overstimulation of these molecular pathways. To study this, the following 5 specific aims are put forth: (1) to characterize the molecular profile of the NMDAR/BDNF system in response to EE rearing in normal and injured animals;(2) to demonstrate that excessive NMDAR activation is the trigger for deleterious molecular changes by blocking the NMDAR at the time of injury and restoring the 'normal'experience-dependent NMDAR/BDNF response;(3) to activate molecular plasticity pathways post-injury through voluntary exercise;(4) to demonstrate that restoring a normal NMDAR/BDNF response results in anatomical and behavioral improvements;and finally (5) to endogenously enhance plasticity at the appropriate time post-injury through exercise, rescue the normal NMDAR/BDNF response, and improve neurobehavioral outcome.
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0.958 |
2009 |
Hovda, David A |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
2nd Joint Symposium of the International and National Neurotrauma Societies @ University of California Los Angeles
DESCRIPTION (provided by applicant): We are requesting support for basic science graduate students, medical students, residents and postdoctoral fellows to participate in the 2nd Joint Symposium of the International and National Neurotrauma Societies to be held September 7 - 11, 2009 in Santa Barbara, California. This symposium is the primary forum for the presentation of current research on the pathophysiology and treatment of central nervous system injury (spinal cord injury, traumatic brain injury). The symposium this year is being co-sponsored and organized by the International Neurotrauma Society, the National Neurotrauma Society, the UCLA Brain Injury Research Center and the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Section on Neurotrauma &Critical Care. The Specific Aims of the symposium are: 1. To provide a forum for the presentation, discussion and feedback regarding the most recent findings in Neurotrauma research and to encourage interaction between junior and senior investigators in the field. 2. To encourage the participation and education of students studying in the field of Neurotrauma. 3. To expand the scope of the sessions to include global perspectives on Neurotrauma, including epidemiology, adherence to practice guidelines, resource limitations and priorities for research. This will be accomplished through the participation of a broad range of international speakers, chairs and investigators. 4. To make the meeting more relevant to clinical neurotrauma researchers and to increase the real world neurotrauma knowledge base for basic neurotrauma scientists by facilitating bidirectional translational sessions. Furthermore, this meeting will provide opportunities for interdisciplinary collaboration and discussion between acute clinical specialties and rehabilitative specialties, industry and academia, and investigators from developing and industrialized nations. 5. To continue to encourage the involvement and advancement of women, minority groups, and persons with disabilities in Neurotrauma research. 6. To have relevant and thought-provoking presentations by researchers not directly involved in Neurotrauma research. The program for the 2009 symposium will feature 28 plenary speakers, 54 breakout speakers, 15 oral presentations by selected student/postdoctoral abstracts, 6 poster sessions with a total of 700 posters and a student poster competition. The symposium will foster basic and translational neurotrauma research that will lead to new techniques for the treatment of patients afflicted with brain and spinal cord injury. PUBLIC HEALTH RELEVANCE: The direct relevance of this project to the public health rests in the exchange of new ideas and debate generated regarding advancing laboratory findings into clinical practice. Students, basic scientists, clinician scientists and practicing clinicians come together to present and discuss their latest discoveries and advancements in the filed of Neurotrauma. Particular efforts are made to actively engage students to participate and interact with leading international and national basic and clinical scientists.
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0.958 |
2009 — 2013 |
Hovda, David A |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Administration and Clinical @ University of California Los Angeles
The administrative structure for this program project resides within the UCLA Brain Injury Research Center (BIRC) under the direction of David A. Hovda, Ph.D. The center will provide administrative support for the current application. Consequently, the current application does not request money for administrative staff or consumable expenses. The UCLA BIRC will also support supplies, equipment (and upgrades), travel, and imaging scans. This allows for the majority of funding provided to this program from NIH to be applied directly to research. As Principal Investigator for this application, Dr. Hovda will be responsible for all aspects of the program. Dr. Neil Martin (Chief of the Division of Neurosurgery) will have a specific role in the leadership of this program project. As Chief of the Division and Director of the UCLA Neurosurgery Residency Program, Dr. Martin will be responsible for maintaining the commitment by the clinical staff and Division administration to the research activities outlined within this proposal. It should be noted that the Division of Neurosurgery will become an independent Department July 1, 2008. Dr. Neil Martin has been named Chairman of the new Department of Neurosurgery at the David Geffen School of Medicine at UCLA. Day-to-day operations of the research outlined within this proposal will be evaluated on a weekly basis. The faculty and staff of the UCLA BIRC meet every Wednesday from 10:00 AM - 12:00 Noon in the Stern Conference room located within the Division of Neurosurgery. This conference room contains audio-visual equipment and computer support providing access to both clinical and basic science databases. During these meetings, all investigators participate in discussions related to all aspects of the program including space allocation, new recruitments, budgets, public relations, scientific merit, teaching, upcoming scientific meetings and publications. In addition to these programmatic issues, all investigators evaluate the current status of research subjects and review the process of alerting the clinical research team of any new traumatically brain injured patients. One BIRC meeting every month is dedicated to patient presentation where all the collected data on an individual subject is presented and discussed. Another meeting every month is dedicated to the presentation of science by one of the key investigators in the program. This schedule assures that basic scientists are exposed to the clinical research and management issues related to human TBI. Conversely, having basic scientists present their research on a monthly basis assures that clinical scientists are exposed to the most current scientific issues related to the neurobiology of TBI. Attendance is recorded and minutes are distributed for each meeting. In addition to these general weekly UCLA BIRC meetings, the Principal Investigators of the individual projects and the leaders of the individual cores make up a "Principal Investigators" Committee. This Committee meets as issues arise that are deemed by Dr. Hovda as inappropriate for general discussion by the entire research staff. These topics include performance evaluations, authorship, interpersonal and ethical issues related to scientific integrity. 1.2 The Overall Mission of the UCLA BIRC The primary mission of the UCLA Brain Injury Research Center (BIRC) is to advance the understanding of the neurobiology of traumatic brain injury through basic and clinical science research in order to develop effective therapies to enhance functional recovery for victims of traumatic brain injury. The purpose of the UCLA Brain Injury Research Center (BIRC) is to maintain a comprehensive basic and clinical scientific program in the field of TBI emphasizing translational research to develop effective therapies for head injured patients. To this end, the UCLA BIRC adheres to the research goal of applying knowledge obtained from basic science studies toward understanding the neurobiology of human TBI. Consequently, a fundamental commitment of the UCLA BIRC is to support technological advances in imaging, neurophysiology, molecular biology, modeling and behavioral neuroscience, which can be applied with equal rigor to experimental animal subjects as well as TBI patients. As such, UCLA maintains a center of excellence where students and faculty can come to receive training in this important endeavor. The technological capability of directly measuring genetic, neurochemical and neurophysiological processes associated with TBI provides a number of specific markers with which potential therapies can be evaluated. This capability of directly measuring the biology targeted by experimental therapies allows for not only evaluating specific scientific hypotheses, but also assures that recovery of function is linked to appropriate neurobiological processes. This concept is extremely important given that the results from repeated studies in the United States and Europe testing potential therapies have been very disappointing. Clearly, relying on traditional outcome measures without the ability to directly measure the proposed mechanisms responsible has limited our ability as a field to make a strong clinical impact to enhance recovery of function. Supporting the recently acquired technological advances in both imaging and in neurochemical measurements of the human brain, the UCLA BIRC is dedicated to relate outcomes to neurobiological substrates targeted for treatment. Consequently, a truly targeted approach to therapy will be developed. The UCLA BIRC has been the driving force behind a fundamental paradigm shift from limiting the understanding of basic mechanisms in animal studies to that of applying molecular imaging to translate basic experiments to the clinic. Having developed this innovative approach to the study of TBI, the BIRC has an obligation to accelerate its clinical and basic science efforts to explore other components of the pathobiology of TBI. Consequently, the allocation of funds from the State of California to the UCLA BIRC continues to provide the support necessary to establish and maintain a core center of excellence for the research of TBI across multiple campuses of the University of California. Recently, funds have been used to establish and maintain state-of-the-art-imaging capabilities for both experimental animals and human TBI patients. These imaging modalities incorporate positron emission tomography (PET), magnetic resonance imaging (MRI), MRI spectroscopy, cerebral microdialysis and computed tomography. Expansion of the basic science initiatives towards development, neuroplasticity and post-injury vulnerability have required advancement of existing programs in neurochemistry, neurophysiology, neurotransplantation, and molecular biology. All of these initiatives and the corresponding technological applications have been focused on the goal of enhancing functional recovery following TBI. As the primary goal of the UCLA BIRC is to effect the treatment of head injured patients, it is critically important that laboratories work in close association with clinical research teams. This allows experiments to be discussed and evaluated thereby fostering the translation of science into the clinical setting which is so vital to making appropriate progress in the field. Furthermore, the UCLA BIRC provides opportunities for training at both the graduate and postgraduate level in order that students acquire the technical and experience necessary for conducting both experimental and clinical research in the field of TBI. Trainees have joined the BIRC for periods of weeks to months from a variety of programs, including: The University of Texas, The University of Kentucky, Virginia Commonwealth University, Uppsala University, Nihon University, Milan University, University of Hannover, Cambridge, Brown, University of Pennsylvania The University of California, San Francisco, The University of California, Davis, The University of California, Irvine, The University of California, San Diego and The University of Pittsburgh. We will continue to accommodate highly motivated trainees whenever possible, tailoring their experiences as closely as their needs and our capabilities allow. Finally, resources of the UCLA BIRC state allocation continue to support the multi-campus University of California Neurotrauma Research Program. 1.3 The University Of California Neurotrauma Research Program A component of the UCLA BIRC state allocation continues to support a research initiative in TBI for the entire University of California system spanning all campuses. This program supports an annual University of California Neurotrauma Symposium, offers assistance for travel expenses for faculty and students wishing to present their research data related to TBI, and to provide supplemental support for individual research projects and workshops on TBI research. The fundamental mission behind this program is to support TBI injury research throughout all campuses of the University of California. Management, support and oversight of this program are the responsibility of the UCLA BIRC under the direction of Dr. David A. Hovda. The specific goals of the research funding are to: 1. Provide funding to encourage both basic and clinical science research into the topic of traumatic brain injury and recovery of function. 2. Develop and support a fellowship program where graduate and post-doctoral students and faculty can attend UCLA in order to receive research training in both clinical and basic scientific methodologies in the field of Neurotrauma. 3. Provide travel fellowships to the National and International Neurotrauma Society meetings. 4. Support an annual University of California Neurotrauma Symposium where research programs throughout the University of California can present their data, foster and discuss collaborations and address funding needs. The administrative structure of the University of California Neurotrauma Research Program includes the UCLA BIRC Executive Committee consisting of the senior leadership of the UCLA Brain Injury Research Center (see above). Funding and policy decisions are made by this committee in order to assure preservation of the BIRC mission and that an appropriate allocation of resources is maintained. The University of California Neurotrauma Advisory Board (see list below) advises the Executive Committee providing advice regarding the annual UC Neurotrauma Symposium, funding1 decisions, intra-campus clinical trials, developing of core facilities and grant development. This board meets on an annual basis in conjunction with the National Neurotrauma meeting and submits to Dr. Hovda minutes with its recommendations. In the spirit of shared governance, the Executive Committee continues to be responsive to the University of California Neurotrauma Advisory Board, assuring appropriate incorporation of all campuses into all of its initiatives. Dr. Hovda (or his representative) visits each campus annually in order to monitor scientific progress, program development and the fostering of young investigators into the field. Members of the University of California Neurotrauma Advisory Board: Dr. Linda Noble-Hauesslein, Professor of Neurosurgery, UC San Francisco Dr. Bruce Lyeth, Professor of Neurosurgery, UC Davis Dr. Paul Muizelaar, Professor and Chair, Neurosurgery, UC Davis Dr. Jeffrey Max, Professor, Psychiatry, UC San Diego In order to assure appropriate dissemination, the UCLA BIRC has developed and maintains a web site (www.birc.ucla.edu) highlighting the specific goals of the University of California Neurotrauma Program as well as providing announcements for upcoming meetings and funding opportunities. Along with the above methods of communication, the UCLA BIRC arranges for visiting lecture programs at each of the corresponding UC campuses thereby providing direct, personal contact to investigators.
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0.958 |
2009 — 2013 |
Hovda, David A |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Tbi-Induced Cerebral Metabolic Depression and Recovery @ University of California Los Angeles
The central theme of this proposal is to identify the metabolic destination of cerebral glucose taken up after traumatic brain injury (TBI), thereby discovering alternative metabolic pathways receptive to interventions (metabolic therapy) to enhance cellular and functional recovery and ultimately change the future of TBI patient management. Two basic science projects will explore these fundamental issues, and are designed to lead as well as complement two clinical projects. Project 1 (Dr. Richard Sutton) addresses the administration of glucose and pyruvate following cortical controlled impact in the rat to examine their impact on cerebral metabolism, cellular protection and outcome. Project 2 (Dr. Mayumi Prins) will study postnatal day 35 and postnatal day 90 rats using the developmental maturation of fuel transporters as an independent variable. Transporters for the fuels glucose, lactate and ketones will be measured in terms of their expression and function. The focus of ketone metabolism is a unique feature in this project as it not only addresses the effect on outcome, but also rigorously studies the appropriate biochemical pathways. Project 3 (Dr. Paul Vespa) addresses the topic of glucose substrate supply for human TBI patients primarily from the perspective of management of serum glucose concentration. Using different levels of insulin therapy, the effect on global and regional cerebral metabolism will be compared to neurochemical and anatomical markers of cell distress. In a creative cross over experimental design preliminary data will be collected for a future clinical trail. Project 4 (Dr. Neil Martin) will utilize the Kety-Schmidt technique to address how glucose is consumed differently in the human injured brain. The investigators within this program will determine the change in the consumption of cerebral glucose, the effects of changes in transporters, and the effects of enhancing or restricting glucose delivery and the potential use of alternative fuels. This program project will be housed within the UCLA Brain Injury Research Center (Dr. David A. Hovda, Director) so as to assure appropriate imaging, administrative and laboratory support.
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0.958 |
2012 — 2014 |
Engel, Jerome None [⬀] Hovda, David A Jensen, Frances E. Pitkanen, Asla Sl |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Exploratory Grant Program in Disease Modification and Prevention in the Epilepsi @ University of California Los Angeles
Bioinformatics; Disease; Epilepsy; Grant; Modification; Prevention; programs;
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0.958 |
2012 — 2014 |
Engel, Jerome None [⬀] Hovda, David A Jensen, Frances E. Pitkanen, Asla Sl |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
The Epilepsy Bioinformatics Study (Epibios) @ University of California Los Angeles
DESCRIPTION (provided by applicant): We propose a planning grant titled the Epilepsy Bioinformatics Study (EpiBioS) to develop a bioinformatics approach to identify reliable epilepsy biomarkers, a critical need for a Center without Walls (CwW) focused on antiepileptogenesis (AEG). Biomarkers of epileptogenesis are needed to limit the study population by identifying those patients at highest risk for epilepsy after a potential epileptogenic brain insult, and to stage the epileptogenic process. Biomarkers of epileptogenicity are needed as surrogate markers in Phase II clinical trials, to document prevention or cure. From existing animal and patient data, we hypothesize that the three most promising classes of biomarkers will be derived from longitudinal studies of electroencephalographic (EEG), neuroimaging, and molecular changes occurring during the process of epileptogenesis, and existing after the development of epilepsy. Furthermore, we anticipate that no single reliable biomarker will emerge, but that predictive power will require a combination of biomarkers. To jumpstart the search for biomarkers we will utilize existing bioinformatics platforms to analyze available multimodality data longitudinally collected from patients and animals during development of epilepsy, and with epilepsy, to identify the most likely individual biomarkers, and/or combinations of biomarkers of epileptogenesis and epileptogenicity, and to determine the best animal models for future studies. Anticipated problems will be addressed at semiannual focused workshops. At the end of this granting period we intend to submit three deliverables: 1) identification and validation of the most likely biomarkers using data derived from ongoing animal and human studies; 2) comprehensive position papers on strategy and problem solving derived from at least six workshops, and 3) an international, multimodality, interactive, open access, bioinformatics grid available for a large prospective clinical study of biomarkers of epileptogenesis and epileptogenicity. We also intend to use the results of this study to inform investigations into the basic mechanisms of epileptogenesis and the search for novel targets for AEG, essential to the CwW, and anticipate this bioinformatics approach to be the future of biomedical research.
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0.958 |
2013 — 2017 |
Hovda, David A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Using Glutamatergic Pharmacotherapy to Optimize Tbi Recovery @ University of California Los Angeles
DESCRIPTION (provided by applicant): Plasticity, the ability of the brain to modify itself in response to its environment, is fundamental to normal development and cognition. Changes in neural activation have important consequences and can interfere with normal plasticity. Traumatic brain injury (TBI) is the single largest cause of death and disability in children and young persons, and leads to developmental delays and cognitive deficits. Experimental studies have shown that perturbations of excitatory neurotransmission occur after TBI in the immature rat, and that these mechanisms may underlie subsequent impairments of environmental neuroplasticity. Recent investigations have delineated a dichotomous role for activation of the N-methyl-D-aspartate receptor (NMDAR), the predominant excitatory neurotransmitter receptor in the brain. Synaptic activation of NMDARs promotes plasticity and cell survival, while extrasynaptic activation impairs plasticity and enhances apoptotic neuronal death. This proposal hypothesizes that glutamatergic pharmacotherapy will restore disrupted molecular and physiological activation after developmental/pediatric TBI, and that treatment efficacy can be monitored using pharmacological MRI (phMRI) as a noninvasive biomarker. This goal will be achieved through the following three specific aims: 1) To measure the balance of critical molecular markers of plasticity and cell death, and establish the translational relationship between these mechanisms and quantifiable physiological functions such as regional cerebral blood volume changes (as measured using phMRI) and behavioral performance, 2) To enhance post-injury plasticity using D-cycloserine, an NMDAR co-agonist, and show specificity for this mechanism by blocking the DCS effect with an NMDAR antagonist, and 3) To restore experience-dependent plasticity after developmental TBI using rational glutamatergic pharmacotherapy. This basic science proposal has implications for future clinical/translational studies, particularly through the development of a noninvasive physiological biomarker (phMRI), and through treatment with an agent already approved for clinical use (D-cycloserine).
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0.958 |