TNF-TNFR1 signaling inhibition for stem cell-based myocardial repair and regeneration

Project Details

Description

Preclinical and available clinical trial studies using bone marrow (BM)-derived stem/progenitor cells for myocardial repair have shown a positive trend towards improvement of cardiac function, however the benefits of these therapies have been modest at best. Emerging evidence suggests that hostile micro-environment in the infarcted myocardium, including persistent inflammation, oxidative damage, excessive cell death and impaired neovascularization, have adverse effects on stem and progenitor cell survival and function. TNF-α, a pro-inflammatory cytokine, is highly expressed in ischemic myocardium and other injured tissues and has long been established to be elevated in patients with heart failure and plays a critical role in the repair and regeneration of damaged ischemic tissue. TNF mediates divergent intracellular signaling pathways through its two receptors, TNFR1 (p55) and TNFR2 (p75). Our published in vivo studies, using specific receptor knock out mice, have demonstrated that a number of negative effects of TNF during ischemic tissue repair including enhanced apoptosis, increased infiltration of inflammatory cells, diminished survival of tissue stem cells and persistent elevated expression of inflammatory cytokines/chemokines is largely mediated by TNFR1. We have also demonstrated that TNF signaling via TNFR2 is protective in ischemic injury models. Whether TNF-TNFR1 signaling directly affects the biology and reparative functions of BM-derived endothelial progenitors (EPC) is not known and warrants an inquiry. Our central hypothesis is that inhibition of TNF-TNFR1 signaling may inhibit multiple negative ionotropic effects of TNF after myocardial ischemia and promote EPC mediated myocardial angiogenesis and repair. The premise of this hypothesis is based upon our published and preliminary studies indicating that inhibition of TNFR1 may present a significantly better therapeutic approach for ischemic tissue repair by modulating the microenvironment conducive to the survival and function of transplanted EPCs. The experiments described in the current proposal are designed to test a series of hypotheses grouped according to the following 2 specific aims: Specific Aim 1 - Elucidate the molecular and signaling mechanisms of TNF-TNFR1-mediated BM-derived EC lineage progenitor cell biology and function. Specific Aim 2 - Determine the role of TNF-TNFR1 signaling in BM-derived EC lineage progenitor cell-mediated myocardial repair and regeneration. (AHA Program: Grant-in-Aid)

StatusFinished
Effective start/end date1/01/1731/12/18

Funding

  • American Heart Association: $154,000.00

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