The developing nervous system undergoes major shifts in neuron number during the period of synaptogenesis. The target tissue appears to have a major influence on the final number of neurons innervating the target region itself. While the mechanism underlying this interaction is not resolved, one strong hypothesis postulates the existence of trophic factors produced in the target region and retrogradely transported back to the projecting neuron. Deprivation of this trophic factor leads to neuron death. The biology of neural trophic factors has been best established in the peripheral nervous system, but has also been extensively investigated in the central nervous system of developing animals and, very recently, in the adult central nervous system. Fetal neural tissue may have significant quantities of trophic substances that might affect adult neuron death. This proposal seeks to define the effects of fetal neural tissue grafts on adult rats using a model of axotomy induced neuron death in the medial forebrain region. Specifically, the temporal and regional parameters of fetal grafts that are important in preventing cholinergic and GABAergic host neuron loss will be investigated. Furthermore, the importance of long term graft survival on host medial forebrain neurons will be assessed. Finally, the cellular components of the graft will be separated to quantify the individual effects of donor glia and donor neurons on host neuron death. By refining the parameters of the graft's effect on the host, it is hoped that the mechanisms underlying axotomy induced neuron death can be studied from a different perspective. The impact this research plan has on health care is derived from recent better understanding of neural events in chronic degenerative neurological disorders such as Parkinson's disease, Huntington's chorea and Alzheimer's disease. Loss of specific neuron populations in those diseases may be linked to loss of trophic substances. Furthermore, degree of recovery from acute neurologic diseases such as head trauma may be based on the extent of delayed neuron death can lead to manipulation of those mechanisms and improve outcome in a wide range of neurologic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS001371-02
Application #
3084364
Study Section
Neurological Disorders Program Project Review A Committee (NSPA)
Project Start
1989-07-01
Project End
1994-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Schmidt, R H; Grady, M S (1995) Loss of forebrain cholinergic neurons following fluid-percussion injury: implications for cognitive impairment in closed head injury. J Neurosurg 83:496-502
Akalan, N; Grady, M S (1994) Angiogenesis and the blood-brain barrier in intracerebral solid and cell suspension grafts. Surg Neurol 42:517-22
Christman, C W; Grady, M S; Walker, S A et al. (1994) Ultrastructural studies of diffuse axonal injury in humans. J Neurotrauma 11:173-86
Leonard, J R; Maris, D O; Grady, M S (1994) Fluid percussion injury causes loss of forebrain choline acetyltransferase and nerve growth factor receptor immunoreactive cells in the rat. J Neurotrauma 11:379-92
Patterson, S L; Grady, M S; Bothwell, M (1993) Nerve growth factor and a fibroblast growth factor-like neurotrophic activity in cerebrospinal fluid of brain injured human patients. Brain Res 605:43-9
Schmidt, R H; Grady, M S (1993) Regional patterns of blood-brain barrier breakdown following central and lateral fluid percussion injury in rodents. J Neurotrauma 10:415-30
Grady, M S; McLaughlin, M R; Christman, C W et al. (1993) The use of antibodies targeted against the neurofilament subunits for the detection of diffuse axonal injury in humans. J Neuropathol Exp Neurol 52:143-52
Domino, K B; Hemstad, J R; Lam, A M et al. (1992) Effect of nitrous oxide on intracranial pressure after cranial-dural closure in patients undergoing craniotomy. Anesthesiology 77:421-5
Michaud, L J; Rivara, F P; Grady, M S et al. (1992) Predictors of survival and severity of disability after severe brain injury in children. Neurosurgery 31:254-64
Anderson, P A; Henley, M B; Grady, M S et al. (1991) Posterior cervical arthrodesis with AO reconstruction plates and bone graft. Spine (Phila Pa 1976) 16:S72-9

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