The human brain harbors neural progenitor cells (NPCs) in the subependymal zone that are capable of generating new neurons and gila into adulthood. Recruitment of this endogenous cell population to replace neurons lost to disease or injury is a desirable goal, since it would circumvent problems associated with invasive transplant therapies using other stem cell sources. In rodents, the application of exogenous neurotrophic molecules can augment native production and migration of new neurons to both normal and novel target regions. Although rodent models of adult neurogenesis are useful, substantial differences exist between rodents and humans regarding brain size and configuration, longevity, and long-term controls of cell proliferation. Moreover, differences between the primate and the rodent progenitor cells may reflect differences in their capacity to respond to exogenous and endogenous factors and generate new neurons in the adult forebrain. Thus it is imperative to investigate issues of cellular replenishment and long-term fate using a large-brained, long-lived primate model that is evolutionarily close to humans. Accordingly, the goal of this proposal is to understand the biology and control of endogenous subependymal NPCs in the adult nonhuman primate brain in order to facilitate neurological treatments that involve neural cell replacement. Specifically, we will (1) characterize the regional distribution of the progenitor pool along the ventricular system, (2) define the precise route(s) of migration of newly generated neuroblasts, and (3) determine the phenotypic identity and survivability of newly generated cells in the adult macaque monkey forebrain. Once characterized, we will (4) determine whether native neurogenesis can be experimentally augmented in the adult primate brain, by using neurotrophic viral vector gene therapy to overexpress neurotrophic molecules in the ventricular region of mature monkeys. Results from these studies will provide fundamental knowledge of the in vivo behavior and regulation of NPCs in the environment of the adult primate brain for future applications toward replacing neurons lost to neurodegenerative diseases or brain injury.
| Kornack, David R; Giger, Roman J (2005) Probing microtubule +TIPs: regulation of axon branching. Curr Opin Neurobiol 15:58-66 |
