2009 — 2011 |
Kartje, Gwendolyn Louise |
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. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Neuronal Plasticity and Recovery of Function After Stroke @ Loyola University Chicago
Principal Investigator/Program Director (Last, first, middle): Kartje, Gwendolyn, L RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? l Yes m No IACUC Approval Date: Animal Welfare Assurance Number A-3117-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or l Yes m No partnership with International Collaborators? 5.b. If yes, identify countries: Switzerland 5.c. Optional Explanation: Professor Schwab is our long time collaborator 6. * Project Summary/Abstract 3700-ProjectSummary.pdf Mime Type: application/pdf 7. * Project Narrative 2916-Relevance.pdf Mime Type: application/pdf 8. Bibliography &References Cited 4695-Literaturecited.pdf Mime Type: application/pdf 9. Facilities &Other Resources 9224-RESOURCES.pdf Mime Type: application/pdf 10. Equipment Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Kartje, Gwendolyn, L Project summary Stroke is a devastating disorder that leads to neuronal death and neurologic disability. The brain's inherent ability to form new neuronal connections and restore lost function can be enhanced by neutralizing the inhibitory nature of the adult CNS through antibody therapy targeting the protein Nogo-A. We have shown that anti-Nogo-A immunotherapy results in neuronal plasticity and functional recovery after ischemic stroke in adult rats. A better understanding of the mechanism underlying anti-Nogo-A immunotherapy would lead to improved therapeutic approaches for clinical use. Additionally, since stroke is more prevalent in the aged, ischemic stroke is best studied in a model which incorporates the aged animal, as we propose here. We hypothesize that interfering with the growth inhibitory protein Nogo-A induces specific genomic changes and enhances functional recovery after stroke by increasing axonal and dendritic plasticity in brain regions important for sensorimotor function. We will test our hypothesis in the following specific aims: Specific aim #1- Determine whether anti-Nogo-A immunotherapy after stroke results in increased axonal and dendritic plasticity in the aged rat. We will also determine the appropriate treatment time for therapy, and examine genomic changes that occur after stroke and anti-Nogo-A therapy in order to better understand the other important gene products important for stroke recovery in our model. Specific aim #2- Determine whether contralesional forelimb cortex mediates recovery after stroke and anti-Nogo-A immunotherapy. We will use both large and small stroke volumes to determine the effects of lesion size on mechanisms of stroke recovery and also use intracortical microstimulation to map the remaining cortical tissue by examining evoked forelimb movements. Specific aim #3- Determine whether global or oligodendrocyte-specific Nogo-A knockout mice demonstrate spontaneous neuroplasticity after ischemic stroke, and also perform genomic analysis to determine other important gene products for plasticity after stroke. The results of these studies will lead to new therapeutic approaches to return lost function to patients suffering from ischemic as well as other causes of brain damage by giving new insight into repair mechanisms in the aged brain, and lead to appropriate design for the translation into clinical trials using anti-Nogo-A immunotherapy after stroke. Project Description Page 6
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1 |
2013 — 2014 |
Kartje, Gwendolyn Louise |
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.) |
The Effects of Binge Ethanol On Neuroinflammation/Functional Recovery After Tbi @ Loyola University Chicago
DESCRIPTION (provided by applicant): Traumatic brain injury is a major cause of death and disability, and many people are under the influence of alcohol at the time of injury, following a pattern of binge alcohol use. Neuroinflammation is a consequence of traumatic brain injury, and alcohol has been shown to have a modulatory effect on the brain inflammatory response through interactions with microglial cells. Additionally, exposure to binge alcohol decreases dendritic complexity of pyramidal neurons in the neocortex, leading to poor performance on behavioral tasks. Therefore, we hypothesize that: Binge ethanol exposure prior to traumatic brain injury will worsen functional outcome and decrease neuronal plasticity due to an increase in the neuroinflammatory response. Aim #1 will determine functional recovery and neuronal plasticity in adult male rats given a binge ethanol regimen followed by traumatic brain injury while acutely intoxicated. We will use sensitive tests of sensorimotor recovery and golgi-cox staining to determine neuronal dendritic plasticity. Aim #2 will determine the neuroinflammatory response in adult rats given a binge ethanol regimen followed by traumatic brain injury while acutely intoxicated. We will determine inflammatory cytokine levels and characterize the microglial cell response in pertinent brain regions.
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1 |
2020 |
Kartje, Gwendolyn Louise |
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. |
Novel Approaches to Stimulating Neurotrophin Signaling For Stroke Recovery @ Chicago Assn For Research & Educ in Sci
Project Summary/Abstract Stroke is a leading cause of adult neurologic disability with survivors often left with permanent deficits due to neuronal loss resulting from ischemia-induced brain injury. There are currently no successful treatments to restore normal function to stroke patients once brain damage has occurred, with the exception of rehabilitation therapy, which is limited in its ability to promote full recovery. In preclinical studies, treatments that stimulate the replacement of damaged pathways with new neuroanatomical connections from uninjured neural tissue, a process known as neuroplasticity, have proven to be promising strategies for improving recovery of function after injury. Our laboratory has used antibody therapy directed at blocking the neurite inhibitory protein Nogo- A to promote neuroplasticity and significantly improve the functional outcome of animals affected by experimental stroke. However, the cellular and molecular mechanisms responsible for anti-Nogo-A antibody- mediated recovery remain largely unknown. We have previously demonstrated that Nogo-A alters nerve growth factor (NGF)-dependent neurotrophin signaling to negatively influence neuronal survival and neurite outgrowth. The goal of this proposal is to verify that disruption of TrkA signaling is a consequence of stroke- induced Nogo-A expression, and to validate approaches designed to re-establish plasticity-promoting neurotrophin signaling by NGF receptors (TrkA and p75NTR). Our central hypothesis is that treatments that circumvent or block Nogo-A inhibition of TrkA to stimulate TrkA-mediated neurotrophin signaling pathways will enhance neuroplasticity and improve recovery following ischemic stroke. In Aim 1 we will use primary neurons in culture to examine TrkA and p75NTR neurotrophin signaling mechanisms affected by Nogo-A and test strategies designed to circumvent or block the inhibitory effect of Nogo-A on TrkA signaling. In Aim 2 we will determine the role of Nogo-A on TrkA-mediated neurotrophin signaling following ischemic stroke in vivo using neuron-specific Nogo-A knockout mice. Biochemical and immunohistochemical techniques will be used to assess the effect of stroke on NGF receptors, their downstream effectors and the association of these receptors with Nogo-A in wild type and knockout mice. In Aim 3 we will evaluate therapeutic interventions that circumvent or block the inhibitory action of Nogo-A on the TrkA receptor to enhance recovery after stroke. We will use our well-studied in vivo stroke model to determine the extent to which treatment with anti-Nogo-A antibody or the novel selective TrkA agonist gambogic amide affects NGF signaling and stroke recovery. Together, the results from this proposal will increase our understanding of underlying neurotrophin-mediated signaling mechanisms altered as a result of stroke injury. Thus, the proposed work will provide a foundation for novel and promising therapies for stroke rehabilitation, which is critically important for the design and successful outcome of future clinical trials.
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0.928 |