Role of Sphingosine Kinase 1 in the Pathogenesis of Idiopathic Pulmonary Fibrosis: Identification of Novel Transcription Factors as Potential Therapeutic Targets by in silico Analysis

Abstract

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no definitive treatment. However, a bioactive lipid mediator, sphingosine-1-phosphate (S1P) has been identified to have a role in the pathogenesis of IPF. S1P is synthesized from sphingosine by iso-enzymes sphingosine kinase (SPHK) 1 & 2. In animal models of IPF, genetic knockout of Sphk1 or inhibition of SPHK1 protected the lungs from fibrosis induced by inciting agents. SPHK1 expression is upregulated in IPF; however, the mechanism(s) of its upregulation remain unclear. Hypothesis In silico analysis can predict transcription factors (TFs) that could bind to the promoter region of mouse Sphk1, upregulating its transcription. This could help predict therapeutic targets for IPF in mouse models. Methods: MatInspector® software tool of Genomatix Inc. (Germany) was used for in silico analysis of TF binding sites in Sphk1. This tool uses the available pool of data for TF binding sites to predict probable binding sites in the DNA nucleotide sequence. Results A search for Sphk1 transcript in mouse using gene ID 20698 with accession numbers GXP_6660985, 9541363 and 10224577 yielded 2,119 matches in chromosome 11. GXP_6660985, with the highest probability of TF binding, was the main transcript. The top 100 TF binding sites were analyzed. Among these, 24 binding sites relevant to lung tissue had a very high probability of binding with matrix similarity of 0.98 to 1.0. The TFs included GREF, STAT, SMAD and FKHD. Among these, seven TFs and their binding sites were not cited in the literature according to MatInspector®. Conclusions: A total of 12 TFs were identified in lung tissue as potential members of transcription initiation complex for Sphk1 gene in mouse.Future direction: In silico analysis of TF binding for human SPHK1 is in progress. Modulation of these TFs could serve as a potential therapeutic tool for IPF. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.