Autophagy-Mediated Responses to Inflammation

Grant Winners

  • Vladimir Beljanski, Ph.D. – CTI
  • Lubov Nathanson, Ph.D. – College of Osteopathic Medicine
  • Nirja Patel, B.S. – Halmos College of Oceanography and Natural Sciences

Deans

  • H. Thomas Temple, Ph.D. – CTI
  • Ellen M. Wallace, D.O., M.S., M.S., M.S. – College of Osteopathic Medicine

Abstract

Autophagy-Mediated Responses to Inflammation

Heart diseases are the leading cause of death among people in industrialized nations, and once a myocardial infarction occurs, no standard treatments exist to reverse the injury. Therefore, we and others are currently investigating the use of human mesenchymal stromal cells (MSC) for repair of heart tissue by injecting MSC into the damaged organ. Using MSC for organ repair carries certain risks, including rejection of injected MSC due to host-derived inflammation responses. Although such risks can be mitigated by immunosuppressant therapies, frequently secondary infections may occur as a consequence of immunosuppression. 

We notice that autophagy, a cellular degradation pathway, also contributes to regulation of inflammation responses by degrading immunomodulatory proteins (cytokines) and/or by regulating the display of small peptide fragments on cellular surface (antigen presentation). Therefore, we hypothesize that pharmacological modulation of autophagy can be utilized to delay or prevent rejection of MSC, by decreasing pro-inflammatory genes and pathways in MSC. Here we propose to examine the role of autophagy in inflammation response using an inflammation model of MSC engraftment.

The goal of Specific Aim 1 is to isolate MSC from umbilical cords and characterize surface antigens of MSC using flow cytometry and differentiate them into cardiac progenitor cells (CPC) using a standard protocol. To accomplish Specific Aim 2, we will expose CPC to a stimulator of inflammatory response, interferon gamma (IFN). Together with IFN, we will add an autophagy stimulator (fluspirilene) or we will inhibit early or late stages of autophagy (3-methyladenine or chloroquine, respectively). Subsequently, we will perform gene expression analysis using the latest state-of-the-art technology RNAseq and subsequent bioinformatics analysis to identify inflammation-related genes/pathways that are perturbed due to autophagy modulation.

Results of this study will contribute to our understanding of the role autophagy plays in response to inflammation in CPC which will also reveal whether targeting autophagy could be used to prevent immune rejection.