Replacement of dopamine (DA) neurons via transplantation of fetal neurons as a therapy for Parkinson's disease has proven effective in some patients. One limitation of this approach is that therapeutic benefit relies upon transplantation of large numbers of cells to overcome poor survival of grafted neurons. One projected solution to this problem is the generation of a nearly inexhaustible supply of DA neurons for transplantation derived from a stem/progenitor cell source. While this has been achieved for cells derivedfrommouse, similar attempts with human cells have not produced significant numbers of DA neurons that retain phenotype following grafting. An altemate approach is not to coerce differentiation to the DA phenotype prior to grafting, but exploit inherent repair properties of stem/progenitor cells. We recently have demonstrated that grafted undifferentiated neural progenitor (NP) cells derived from embryonic rat rescue adult substantia nigra (SN) neuronsfromdegeneration following intrastriatal injection of 6- hydroxydopamine. The goal of this proposal is to document characteristics of the biology of this effect and begin to evaluate the clinical relevance of this approach by expanding our analysis to include study of human NP cell lines. Specifically we will 1) track the phenotypic fate of grafted NP cells and host SN neurons and glia over time after lesion and grafting. 2) Perform an initial study of potential mechanisms of mNP cell-induced neuroprotection by decreasing expression of the neurotrophic factors BDNF and PTN, using RNAi, in cells prior to grafting. 3) Determine whether neuroprotection is correlated with changes in additional factors associated with nigral cell injury: pro-inflammatory cytokines, apoptosis factors, neurotrophic factors and changes in DA metaboUsm as measured by PCR-based array and HPLC, to provide future targets for mechanistic studies. 4) Localize mRNA changes for relevant molecules to specific cell populations within the graft and host using in situ hybridization. 5) Determine whether NP cells remain effective in aged rats. The relative therapeutic efficacy and characteristics of NP cells from rat and human will be compared and contrasted in this neuroprotection paradigm. Implantation of undifferentiated NP cells may provide a simple, effective strategy for inducing neiu-al protection and repair.
(See Instructions): The findings of this project will provide important information relevant for the design of an optimal stem/progenitor cell therapy for treatment of Parkinson's disease.
|Polinski, Nicole K; Gombash, Sara E; Manfredsson, Fredric P et al. (2015) Recombinant adenoassociated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain. Neurobiol Aging 36:1110-20|
|Gombash, S E; Manfredsson, F P; Mandel, R J et al. (2014) Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways. Gene Ther 21:682-93|
|Hemmerle, A M; Dickerson, J W; Herman, J P et al. (2014) Stress exacerbates experimental Parkinson's disease. Mol Psychiatry 19:638-40|
|Levine, Nathan D; Rademacher, David J; Collier, Timothy J et al. (2013) Advances in thin tissue Golgi-Cox impregnation: fast, reliable methods for multi-assay analyses in rodent and non-human primate brain. J Neurosci Methods 213:214-27|
|Madhavan, Lalitha; Daley, Brian F; Sortwell, Caryl E et al. (2012) Endogenous neural precursors influence grafted neural stem cells and contribute to neuroprotection in the parkinsonian rat. Eur J Neurosci 35:883-95|
|Hemmerle, Ann M; Herman, James P; Seroogy, Kim B (2012) Stress, depression and Parkinson's disease. Exp Neurol 233:79-86|
|Gombash, Sara E; Lipton, Jack W; Collier, Timothy J et al. (2012) Striatal pleiotrophin overexpression provides functional and morphological neuroprotection in the 6-hydroxydopamine model. Mol Ther 20:544-54|
|Spieles-Engemann, Anne L; Steece-Collier, Kathy; Behbehani, Michael M et al. (2011) Subthalamic nucleus stimulation increases brain derived neurotrophic factor in the nigrostriatal system and primary motor cortex. J Parkinsons Dis 1:123-36|
|Kordower, Jeffrey H; Dodiya, Hemraj B; Kordower, Adam M et al. (2011) Transfer of host-derived * synuclein to grafted dopaminergic neurons in rat. Neurobiol Dis 43:552-7|
|Soderstrom, Katherine E; O'Malley, Jennifer A; Levine, Nathan D et al. (2010) Impact of dendritic spine preservation in medium spiny neurons on dopamine graft efficacy and the expression of dyskinesias in parkinsonian rats. Eur J Neurosci 31:478-90|
Showing the most recent 10 out of 12 publications