Our studies have established that there is an early regenerative response initiated by the neural stem cells and progenitors (NSPs) in the subventricular zone (SVZ) in response to a perinatal hypoxic-ischemic (H-I) insult and that the expansion of the NSPs requires the cytokine leukemia inhibitor factor (LIF). We have collected new data that reveals other functions of LIF as LIF haplodeficient animals sustain worse injury compared to wild type mice. Complementing those loss of function studies, we provide preliminary data to show that delayed intranasal LIF administration, reduces the extent of cerebral neuronal loss, increases proliferation in the SVZ and improves neurological function in a mouse model of near term hypoxia-ischemia. Therefore, the premise of this proposal is that LIF is an essential neuroprotective and regenerative cytokine and that the non-invasive, intranasal administration of LIF can promote regeneration and decrease the long-term burden of neurological deficits. We will test this premise by performing experiments using pre-term and near-term mouse models of perinatal injury with the following 3 specific aims: 1) that LIF haplodeficient mice will sustain greater neuronal and glial cell damage after a developmental brain injury accompanied by worse neurological disabilities; 2) that delayed intranasal LIF administration will stimulate the numbers of stem cells and progenitors to repair the damaged gray and white matter and 3) that the extent of axonal regeneration and function can be improved by delayed intranasal LIF administration. During the course of our studies we will elucidate the mechanisms through which LIF is exerting its potent neuroprotective and regenerative actions. As it is likely that many perinatal insults occur during the antenatal period and go undetected, the knowledge obtained from these studies could lead to therapeutics that could be administered to infants subacutely to enable the damaged brain to develop normally from its endogenous stem cells, thus decreasing the incidence and life long cognitive, motor and emotional handicaps that occur as a result of developmental brain damage.

Public Health Relevance

Despite progress in reducing the extent of injury after perinatal hypoxic-ischemic brain injury, there are presently no approved therapeutics to both reduce the extent of secondary injury and promote regeneration. The goal of this proposal is to use a mouse model of perinatal hypoxic-ischemic brain injury to test the therapeutic efficacy of a cytokine that we hypothesize will both preserve injured neurons and stimulate the replacement of damaged neurons and glia from the resident neural stem cells of the subventricular and subgranular zones.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS116828-01A1
Application #
9980145
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Koenig, James I
Project Start
2020-04-01
Project End
2025-02-28
Budget Start
2020-04-01
Budget End
2021-02-28
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Rutgers University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103