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Brain and Spinal Cord Trauma
Traumatic brain injury (TBI) is the leading cause of acquired brain damage in children, producing persistent functional disability. The response to and recovery from TBI differs in adults and children. Brain damage from TBI is determined not only by direct mechanical injury to neural structures, but also by delayed axonal degeneration and neuronal apoptosis. The overall goal of this research project is to determine if fundamental differences in the molecular pathways that produce neuronal death are related to brain maturity. Tae Chang, MD, in collaboration with Alan Fadden, MD, (Georgetown University), established an animal model of traumatic brain injury for translational intervention studies. Gerard A. Gioia, PhD, received a Department of Defense (DOD) grant to adapt cognitive rating scales established to assess adults following TBI to young children. Penny Glass, PhD, is conducting a study that demonstrates the catastrophic effects of TBI during infancy on cognitive function and developmental outcome. Phillip L. Pearl, MD, and John N. Van Den Anker, MD, PhD will provide the Children's staffing of a RO1 award (with Pavel Klein MD, of Washington Hospital Center, PI) to perform a feasibility and phamacokinetic study of leviteracitam, a new anti-epileptic drug (AED) in preventing epilepsy in mild TBI.
Traumatic Brain Injury
Traumatic brain injury is one of leading causes of morbidity and mortality in pediatric populations, and subsequent, delayed neuronal death in subcortical structures contributing to functional damage. Expression profiling the time-dependent responses to cortical injury can contribute important insights regarding potential protective mechanisms in delayed neuronal death. However, information obtained to date is seriously compromised by failure to specifically isolate neurons from their mixed cellular environment. This problem is compounded by the fact that degenerating neurons constitute a small proportion of cells in the target tissue. Current approaches to resolving these problems emphasize microanatomical techniques, each of which has substantial limitations. We have assembled an integrative, multidisciplinary team to provide an alternative approach based on novel applications of computational neurobiology. Although on faculty at different institutions, team members work in the same metropolitan area and have a demonstrated record of successful collaboration. JoAnne Elizabeth Natale, MD, PhD is a neuroscientist who has developed a reliable method for inducing both primary and secondary brain injury and for expression profiling responses over time in subcortical (thalamic) structures. Her work has demonstrated that metallothionein mitigates neuronal death after brain injury. Drs. Wang and Xuan are computer engineers who have identified computational methods for tissue heterogeneity correction of mRNA expression data. Finally, Eric P. Hoffman, PhD, in the Center for Genetic Medicine has been a leader in providing high-quality, web-queried expression profiling databases containing hundreds of human, mouse and rat expression profiles.
Activities to be undertaken in this proposal, include: 1) the use cell-specific gene profiles to train the computational algorithm partially-independent component analysis (PICA) to separate neuronal from microglial gene expression profiles during secondary brain injury; 2) verify the performance of the tissue heterogeneity correction of PICA by mixing known ratios of neurons, microglia and remaining tissue isolated from injured thalamus at specific time points after injury; and 3) determine if minocycline represses the microglial-specific expression of cytotoxic factors or the induction of neuron-specific cytoprotective factors in MT-deficient mice after brain injury.
Neurofibromatosis
More than 50 percent of individuals with neurofibromatosis 1 (NF1) have cognitive deficits, such as learning disorders and attention deficit/hyperactive disorder that are neuroanatomically unrelated to the neurofibromas. The molecular basis for these cognitive deficits remain undefined. We hypothesized that the cognitive deficits in NF1 are due to developmental alterations initiated as a result of the primary gene mutation but are unrelated to the tumor suppressor effects of neurofibromin. We tested this hypothesis by examining the developmental transcripsome of mice with neurofibromin haploinsufficiency. These NF mice develop learning and memory difficulties that mimic humans, but are not predisposed to the development of tumors. In our research effort we found significant downregulation of certain KIF genes and cytoplasmic linker protein and upregulation of other genes. Protein levels were consistent with the mRNA levels except for certain KIF genes. KIFs are crucial for the transport synaptic vesicle precursors to the synapse and for dendritic branching. Disruption in these transport processes may result in imparted synaptic transmission that contribute to the cognitive deficits associated with NF1 (Data are available at http://pepr.cnmcresearch.org. We aim to study the biological basis of Neurofibromatosis.
Activities to be undertaken include: 1) The use of cell-specific gene profiles to train the computational algorithm partially-independent component analysis (PICA) to separate neuronal from microglial patterns during secondary brain injury; 2) Verification of the performance of the tissue heterogeneity correction of PICA by mixing known ratios of neurons, microglia and remaining tissue isolated from injured thalamus at specific time points after injury; and 3) The determination if minocycline represses the microglial-specific expression of cytotoxic factors or the induction of neuron-specific cytoprotective factors in MT-deficient mice after brain injury.
Related Links
Brain Injury Association of America (formerly National Head Injury Foundation)
www.biausa.org
Provides information to educate the public, policians, businesses, and educators about brain injury, including effects, causes and prevention.
Traumatic Brain Injury Resource Guide
www.neuroskills.com
Web site includes educational information, books, local support groups, and research.
Medline
www.ncbi.nlm.nih.gov
Contact Information:
Nikkie Adesida
Children's Research Institute
Center for Neuroscience Research
Children's National Medical Center
111 Michigan Avenue, NW
Washington, DC 20010
202-476-2389
202-476-4988 fax
nadesida@cnmcresearch.org
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