We have recently established that there is an early regenerative response initiated by the neural stem cells (NSCs) in the subventricular zone (SVZ) in response to a perinatal hypoxic/ischemic (H/I) insult; therefore, the goals of this proposal are to establish the molecular mechanisms responsible for this adaptive change and to determine whether we can amplify this response. Preliminary data indicate that: 1) there is increased proliferation within the SVZ within the region that is known to contain the NSCs; 2) there is a transient increase in the abundance of multipotential NSCs after perinatal H/I; 3) NSCs placed in vitro retain a memory of the insult; and 4) these cellular changes are accompanied by changes in the expression of several ligands and receptors that have been implicated in stem cell maintenance. To our knowledge, these are the first available data demonstrating that there is a change in the numbers of multipotential NSCs as a consequence of any insult to the CNS. Consequently, the overall hypothesis of this application is that there is an increase in the number of stem cells in the H/I brain as a consequence of both intrinsic changes within the stem cells as well as extrinsic changes to their niche. The following specific aims are proposed:
Aim 1 : To determine the magnitude and kinetics of the stem cell response to perinatal H/I;
Aim 2. To test the hypothesis that brain damage increases the frequency of symmetrical NSC amplifying cell divisions;
Aim 3 : To identify the molecules that amplify neural stem cell numbers after perinatal H/I;
Aim 4 : To determine whether LIF or Notch1 receptors regulate NSC numbers after H/I;
Aim 5. To determine whether the increased abundance of neural stem cells is a consequence of a direct effect on the cells or whether this increase is a result of changes to the stem cell niche. As there is great interest in exploiting stem cells for CNS regeneration, completion of the proposed studies will enhance our fundamental understanding of the signals that maintain these precursors as neural stem cells and which signals regulate their abundance in vivo. It must be emphasized that at the present time, there are no therapies available to protect the infant brain from perinatal insults or stimulate regeneration. Moreover, as it is likely that the majority of perinatal insults occur during the antenatal period and that such events occur undetected, the knowledge obtained from these studies could eventually lead to therapeutics that could be administered to infants to enable the damaged infant brain to develop normally from its endogenous stem cells. Such therapies would clearly have advantages over transplantation approaches, and if effective would decrease the incidence and life long cognitive, motor and emotional handicaps that occur as a result of perinatal brain damage.
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