The ultimate goal of this research is to understand the mechanisms of regeneration and repair of cell injury. The proximal tubule is one tissue that is capable of regeneration. We and others have observed that regeneration of the proximal tubule can be stimulated by the addition of epithelial growth factor (EGF). Others have also used a mouse model of acute renal failure to demonstrate that EGF receptor (EGFR) activation is necessary for recovery. The contribution of the EGFR to this regeneration response is not fully understood. Also, the development of EGF analogs for the therapeutic induction of the regeneration response has not been attempted. We propose to elucidate the contribution of EGF to the regeneration response and develop a potential therapeutic that induces a similar response.
Specific Aim 1 will characterize EGFR expression and activation following injury and during regeneration in both an in vitro model and an animal model of acute renal failure (ARF).
Specific Aim 2 will develop a series of peptide agonists with high affinity for the EGFR using phage display technology. We will focus on producing a kinetically stable analog to promote usefulness in vivo systems.
Specific Aim 3 will evaluate the EGFR peptide agonist(s) obtained from Specific Aim 2 for therapeutic efficacy in an in vitro model and an animal model of ARF. ? ?
| Hallman, Mark A; Zhuang, Shougang; Schnellmann, Rick G (2008) Regulation of dedifferentiation and redifferentiation in renal proximal tubular cells by the epidermal growth factor receptor. J Pharmacol Exp Ther 325:520-8 |
