The nigrostriatal dopamine system is one important brain pathway involved in the coordination of movement control. For reasons that remain unknown, that system degenerates in Parkinson's disease. In the proposed studies, neural grafting techniques are adopted in an attempt to compensate for a genetically-determined nigrostriatal dopamine deficiency that is found in weaver mulani mice. The abnormality of the nigrostriatal dopamine projection, which is caused by a recessive mutant gene, renders the homozygous weaver mouse a parlicularly valuable model in understanding pathogenetic mechanisms of dopamine neuron degeneration and in designing and testing transplantation methodologies for the correction of the neurological deficit by replacing missing cells with homologous donor tissue. In particular, the issues addressed include the ability of the grafts to sustain an anatomical and functional innervation of the host for the longest possible survival-time; the specifically of the reconstructed neuronal circuit that is formed by graft-derived afferents in the recipient brain; the mechanisms of neurotransmitter function in the graft-induced anatomical condition; and the potential of the grafts for the correction of specific behaviors at the organism level, which require a precise rewiring of the neuronal network. The proposed goals will be achieved by combining a mullitude of neurobiological techniques, including neural grafting, histology, optical and ultrastructural immunocytochemisiry, neurochemistry, neuropharmacology, and behavioral analysis. Particular reference is made to the integration of healthy donor cells with the pathologic nervous system of the genetically-mutant host. The experiments proposed will provide fundamental information pertinent to the design of strategies and to the effects of therapeutic intervention in degenerative brain disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS029283-02
Application #
3478241
Study Section
Pathology A Study Section (PTHA)
Project Start
1991-01-01
Project End
1995-12-31
Budget Start
1992-01-01
Budget End
1992-12-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Stasi, K; Mitsacos, A; Triarhou, L C et al. (1997) Cerebellar grafts partially reverse amino acid receptor changes observed in the cerebellum of mice with hereditary ataxia: quantitative autoradiographic studies. Cell Transplant 6:347-59
Triarhou, L C; Zhang, W; Lee, W H (1996) Amelioration of the behavioral phenotype in genetically ataxic mice through bilateral intracerebellar grafting of fetal Purkinje cells. Cell Transplant 5:269-77
Zhang, W; Lee, W H; Triarhou, L C (1996) Grafted cerebellar cells in a mouse model of hereditary ataxia express IGF-I system genes and partially restore behavioral function. Nat Med 2:65-71
Triarhou, L C (1996) The cerebellar model of neural grafting: structural integration and functional recovery. Brain Res Bull 39:127-38
Triarhou, L C; Sola, C; Mengod, G et al. (1995) Ventral mesencephalic grafts in the neostriatum of the weaver mutant mouse: structural molecule and receptor studies. Cell Transplant 4:39-48
Triarhou, L C; Zhang, W; Lee, W H (1995) Graft-induced restoration of function in hereditary cerebellar ataxia. Neuroreport 6:1827-32
Witt, T C; Triarhou, L C (1995) Transplantation of mesencephalic cell suspensions from wild-type and heterozygous Weaver mice into the denervated striatum: assessing the role of graft-derived dopaminergic dendrites in the recovery of function. Cell Transplant 4:323-33
Triarhou, L C; Norton, J; Hingtgen, J N (1995) Amelioration of the behavioral phenotype in weaver mutant mice through bilateral intrastriatal grafting of fetal dopamine cells. Exp Brain Res 104:191-8
Stotz, E H; Palacios, J M; Landwehrmeyer, B et al. (1994) Alterations in dopamine and serotonin uptake systems in the striatum of the weaver mutant mouse. J Neural Transm Gen Sect 97:51-64
Triarhou, L C; Stotz, E H; Low, W C et al. (1994) Studies on the striatal dopamine uptake system of weaver mutant mice and effects of ventral mesencephalic grafts. Neurochem Res 19:1349-58

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