Perinatal hypoxia-ischemia (HI) is a major cause of life-long neurological disability such as cerebral palsy. There are few treatments available for this devastating disorder. For the next period of support we propose to study more in-depth of a novel molecular target of HI brain injury based on our new and exciting findings during the last funding period that neuronal pentraxin I (NP1), a member of a subfamily of "long pentraxins", is induced in HI brain injury. Our hypothesis is that induction of NP1 is part of the molecular cascade of cell death program involved in HI brain injury potentially via diverse mechanisms of action.
In Aim 1, we will use the wild type (WT) and NP1 knockout (NP1-KO) mice in our neonatal mice model of HI to examine NP1 induction in WT brain, and the magnitude of injury in different brain areas of WT vs. NP1-KO mice to determine the temporal and regional pattern of NP1 induction specific to injury. Next, we will use NP2 (also called Narp)-KO and NP-triple KO (NP1, NP2 and NP-receptor are all knocked out) mice to examine if NPs can compensate for one another in HI brain injury. To demonstrate specific involvement, we will examine NP1, NP2 and NPR induction in WT primary neuronal cultures, and neuronal death (WT vs. KO) at different time periods of oxygen and glucose deprivation (OGD). Next, we will apply a gain-of-function strategy to individually reintroduce NP1 or NP2 into the NP1-KO, NP2-KO and NP-TKO neuronal cells before OGD exposure. Comparisons of results will directly determine the specific requirement of NP1 induction and will further establish if NPs can compensate for one another in the injury mechanism. Results will reveal a causal role of NP1 in HI brain injury.
Aim 2, will examine whether altering NP1 and NP2 functions alter AMPA-and NMDA-receptor-mediated excitotoxicity using NP1-KO, NP2-KO and NP-TKO mice and compare to that in WT animals. Results will determine the relative contribution of NP1 and NP2 in AMPA and NMDA receptors-mediated excitotoxicity. Next, we will use WT vs. individually knockout (NP1-KO, NP2-KO and NP-TKO) neuronal cultures to examine if the colocalization and binding interactions of NPs with specific receptor subunit are required for cell death. Results will explain how NP1 contributes to neuronal death.
Aim 3, will determine how NP1 induction is regulated. We will apply loss-of- function strategies in WT neuronal cultures to inhibit the prodeath intracellular signaling kinase GSK-3a/? and the transcription factor AP-1 functions. Results will elucidate the specific involvement of GSK-3a/? and the role of AP-1 in NP1 and potentially NP2 and NPR expression. Finally, we will perform the promoter analysis of NP1 gene to identify transcription initiation site and transcription factor(s) involve in the regulation of NP1 induction in brain injury. Our expectations are that at the end of the proposed period of support, we will have elucidated a new mechanism of hypoxic-ischemic brain injury. Our findings will contribute to new strategies for clinical management of neonates suffering from hypoxic-ischemic insults.
Neonatal hypoxia-ischemia due to insufficient supply of oxygen and poor cerebral blood flow reaching the fetal or newborn brain is the major cause of substantial neurological disability such as cerebral palsy in surviving infants and children. There are few treatments available for this devastating neurological disorder. This proposal will explore a new mechanism underlying this condition. Our research will contribute to understand how brain injury occurs and how to prevent the harmful consequences of hypoxia-ischemia induced brain damage in children. Our findings will contribute towards the development of preventive or therapeutic interventions for this major human health problem in the United States and in the world.
|Sharma, Jaswinder; Johnston, Michael V; Hossain, Mir Ahamed (2014) Sex differences in mitochondrial biogenesis determine neuronal death and survival in response to oxygen glucose deprivation and reoxygenation. BMC Neurosci 15:9|
|Al Rahim, Md; Thatipamula, Shabarish; Hossain, Mir Ahamed (2013) Critical role of neuronal pentraxin 1 in mitochondria-mediated hypoxic-ischemic neuronal injury. Neurobiol Dis 50:59-68|
|Al Rahim, Md; Hossain, Mir Ahamed (2013) Genetic deletion of NP1 prevents hypoxic-ischemic neuronal death via reducing AMPA receptor synaptic localization in hippocampal neurons. J Am Heart Assoc 2:e006098|
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