We have found that adenoviral overexpression of BDNF in the adult rodent ventricular system induces the recruitment of new striatal neurons from the progenitor cell pool of the forebrain subependyma. The new striatal neurons project to the globus pallidus and adopt a DARPP32/GABAergic/calbindin+ phenotype, characteristic of medium spiny projection neurons. This is the major neostriatal phenotype lost in Huntington's Disease (HD); as such, the induced regeneration of these cells may be a feasible strategy for moderating disease progression. We also noted that the numbers of new neurons recruited to the striatum in response to BDNF could be greatly potentiated by suppressing gliogenesis, using adenoviral overexpression of noggin, a soluble antagonist of the pro-gliogenic bone morphogenetic proteins (BMPs). On this basis, this proposal asks if induced striatal neuronal recruitment might offer therapeutic benefit in murine models of Huntington's Disease. We have already noted that the R6-2 mouse, a transgenic model of Huntington's disease, indeed harbors competent striatal progenitor ceils, that these give rise to striatal neurons in response to intraventricular AdBDNF, and this process is potentiated by AdNoggin. On this basis, we now ask: 1) Does spontaneous neuronal recruitment occur in HD mice, in response to striatal neuronal loss? Are new neurons recruited in response to striatal apoptosis? What cellular and molecular signals elicit neuronal recruitment? 2) What is the lifespan and connectivity of AdBDNF/Noggin-induced striatal neurons in R6-2 nice? As what transmitter and functional phenotypes do these neurons integrate? 3) Does AdBDNF/AdNoggin-induced neuronal addition prolong the survival of R6-2 mice? Does it slow their motor deterioration? To what extent is AdBDNF/Noggin's effect due to neuronal addition, as opposed to AdBDNF-dependent neuroprotection'? Can the survival of BDNF/noggin-treated R6-2 mice be further improved by histone deacetylase inhibition, as a potentially synergistic neuroprotective strategy? 4) Is sustained BDNF and noggin expression required to maintain neuronal recruitment at levels sufficient to compensate for loss due to Huntington's disease? With what vector systems might this best be accomplished? Does the striatal progenitor pool deplete with sustained stimulation? 5) Can noggin and BDNF be used to induce meaningful levels of neuronal recruitment in the adult primate? Can AdBDNF/AdNoggin-treatment mediate the replacement of striatal neurons lost following treatment with ibotenic acid (IA)? If successful, these experiments should provide both a conceptual and operational foundation for the evaluation of induced striatal neurogenesis as a therapeutic strategy in Huntington's Disease, while providing new insight into the mechanistic bases for both compensatory and induced neurogenesis in the adult mammalian brain. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052534-02
Application #
7091473
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Oliver, Eugene J
Project Start
2005-07-15
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$352,273
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Goldman, Steven A (2016) Stem and Progenitor Cell-Based Therapy of the Central Nervous System: Hopes, Hype, and Wishful Thinking. Cell Stem Cell 18:174-88
Nedergaard, Maiken; Goldman, Steven A (2016) BRAIN DRAIN. Sci Am 314:44-9
Han, Xiaoning; Chen, Michael; Wang, Fushun et al. (2013) Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 12:342-53
Chen, Z; Ye, R; Goldman, S A (2013) Testosterone modulation of angiogenesis and neurogenesis in the adult songbird brain. Neuroscience 239:139-48
Benraiss, Abdellatif; Toner, Michael J; Xu, Qiwu et al. (2013) Sustained mobilization of endogenous neural progenitors delays disease progression in a transgenic model of Huntington's disease. Cell Stem Cell 12:787-99
Iliff, Jeffrey J; Wang, Minghuan; Liao, Yonghong et al. (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid ?. Sci Transl Med 4:147ra111
Benraiss, A; Bruel-Jungerman, E; Lu, G et al. (2012) Sustained induction of neuronal addition to the adult rat neostriatum by AAV4-delivered noggin and BDNF. Gene Ther 19:483-93
Oberheim, Nancy Ann; Goldman, Steven A; Nedergaard, Maiken (2012) Heterogeneity of astrocytic form and function. Methods Mol Biol 814:23-45
McClain, Crystal R; Sim, Fraser J; Goldman, Steven A (2012) Pleiotrophin suppression of receptor protein tyrosine phosphatase-?/? maintains the self-renewal competence of fetal human oligodendrocyte progenitor cells. J Neurosci 32:15066-75

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