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An Investigation of Gene Pathways Indicating Neuregulin-1 Immunoregulation Following Ischemic Stroke

  • Author(s): Hoque, Dian Mirfat
  • Advisor(s): Ford, Byron
  • et al.
Abstract

Stroke is the fifth leading cause of death and the leading cause of adult disability in the United States, but despite this alarming statistic, there are few treatment options for stroke patients, limited by the critical time window during and after a stroke event. Neuregulin-1 (NRG-1), a pleiotropic growth factor belonging to a larger family of neuregulins, has demonstrated a neuroprotective role following ischemic stroke including the regulation of pro-inflammatory processes. In this study, we follow gene expression profiles for rats induced with middle cerebral arterial occlusion (MCAO) to model ischemic stroke; these rats were randomly allocated to three groups, (1) SHAM (2) MCAO and vehicle treatment (MCAO) and (3) MCAO and NRG-1 treatment (NRG), to analyze the mechanisms of NRG-1’s neuroprotective role following ischemic stroke. Temporal gene expression was analyzed as these rats were sacrificed to collect their cortical brain tissues at either 3, 6, or 12 hours post-MCAO; SHAM mice were sacrificed at 3 hours following surgery. The samples were subjected to microarray analysis and the results were analyzed by Transcriptome Analysis Console (TAC), version 4.0 to identify differentially regulated genes as either temporally downregulated or upregulated. These genes were then further analyzed using Qiagen’s Ingenuity Pathway Analysis (IPA) software. A subset of these genes were mapped based on IPA’s Rattus norvegicus genome database and canonical pathways were generated which identified the differentially regulated genes in a variety of canonical gene pathways. Eight of these genes were selected to be discussed in greater detail by comparison of specific gene pathways between MCAO vs. SHAM and NRG vs. SHAM at 3, 6, and 12 hours. These genes were Elk1, Fos, Hmox1, Jun, Mef2, Socs3, Csk, and Vegf, which were identified across multiple pathways, indicating possible regulation by NRG-1. Identifying specific genes and noting potentially significant upstream regulators based on differential gene expression can better improve our understanding of the neuroprotective role of NRG-1 following ischemic stroke.

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