Reconstitution of the damaged neural circuitry in the adult central nervous system (CNS) using fetal neural grafts has considerable promise for treating neurodegenerative diseases. However, this strategy affects only moderate recovery in patients with advanced neurodegenerative diseases, consistent with poor survival of grafts and diminished graft-host integration observed in animal models of chronic brain injury. Thus, evaluation of the efficacy of neural grafting strategies that have potential to enhance both graft integration and graft-mediated functional recovery in the chronically injured brain is of profound importance. The major goal of this project is to develop an ideal neural grafting strategy that facilitates both structural and functional repair of the kainic acid lesioned adult rat hippocampus when applied at 4-months post-lesion, a model of temporal lobe epilepsy (TLE). This paradigm is equivalent to the human application of grafting for chronic TLE. The 1st hypothesis is that pre-treatment and grafting of gestation day (GD) 19 hippocampal CA3 cells with caspase inhibitor and/or specific neurotrophic factors enhances both structural repair and functional recovery mediated by grafts in the chronically injured adult hippocampus. The 2nd hypothesis is that grafts of both younger fetal (i.e. GD17) hippocampal CA3 cells and immature hippocampal CA3 region stem cells are also competent for exhibiting enhanced integration and facilitating functional recovery in the chronically injured adult hippocampus. These hypotheses will be tested with a comprehensive set of quantitative parameters. This will include the following measurements. (1) Graft cell survival. (2) Efferent graft projections to local host sites and appropriate distant sites. (3) Afferent mossy fiber projections to grafts. (4) The extent of graft-mediated: (i) retraction of host aberrant mossy fiber sprouting; (ii) restoration in the number of host GABA-ergic interneurons; (iii) normalization of calbindin protein expression in the host hippocampus; and (iv) the degree of suppression of spontaneous recurrent motor seizures. Identification of strategies that enhance both graft integration and appropriate functional repair of the chronically injured adult hippocampus is of significant relevance for developing graft-mediated therapy for chronic temporal lobe epilepsy. These studies also have implications for the treatment of other neurodegenerative conditions such as stroke and head injury. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043507-04
Application #
7084631
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Fureman, Brandy E
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$321,440
Indirect Cost
Name
Duke University
Department
Surgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Upadhya, Dinesh; Hattiangady, Bharathi; Shetty, Geetha A et al. (2016) Neural Stem Cell or Human Induced Pluripotent Stem Cell-Derived GABA-ergic Progenitor Cell Grafting in an Animal Model of Chronic Temporal Lobe Epilepsy. Curr Protoc Stem Cell Biol 38:2D.7.1-2D.7.47
Shetty, Ashok K (2014) Hippocampal injury-induced cognitive and mood dysfunction, altered neurogenesis, and epilepsy: can early neural stem cell grafting intervention provide protection? Epilepsy Behav 38:117-24
Shetty, Ashok K; Hattiangady, Bharathi (2013) Postnatal age governs the extent of differentiation of hippocampal CA1 and CA3 subfield neural stem/progenitor cells into neurons and oligodendrocytes. Int J Dev Neurosci 31:646-56
Hattiangady, Bharathi; Shetty, Ashok K (2011) Neural stem cell grafting in an animal model of chronic temporal lobe epilepsy. Curr Protoc Stem Cell Biol Chapter 2:Unit2D.7
Hattiangady, Bharathi; Shetty, Ashok K (2010) Decreased neuronal differentiation of newly generated cells underlies reduced hippocampal neurogenesis in chronic temporal lobe epilepsy. Hippocampus 20:97-112
Kuruba, Ramkumar; Hattiangady, Bharathi; Shetty, Ashok K (2009) Hippocampal neurogenesis and neural stem cells in temporal lobe epilepsy. Epilepsy Behav 14 Suppl 1:65-73
Hattiangady, Bharathi; Rao, Muddanna S; Shetty, Ashok K (2008) Grafting of striatal precursor cells into hippocampus shortly after status epilepticus restrains chronic temporal lobe epilepsy. Exp Neurol 212:468-81
Hattiangady, Bharathi; Shetty, Ashok K (2008) Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus. Neurobiol Aging 29:129-47
Acharya, Munjal M; Hattiangady, Bharathi; Shetty, Ashok K (2008) Progress in neuroprotective strategies for preventing epilepsy. Prog Neurobiol 84:363-404
Shetty, Ashok K; Rao, Muddanna S; Hattiangady, Bharathi (2008) Behavior of hippocampal stem/progenitor cells following grafting into the injured aged hippocampus. J Neurosci Res 86:3062-74

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