Although several therapeutic options to treat chronic diabetic wounds exist, ranging from occlusive dressings,vacuum assisted closure, skin grafts, to bioengineered skin substitutes, in many instances the wounds fail toadequately respond to treatment. Chronic wounds are characterized by a failure to progress from the pro-inflammatory to the proliferative phases of wound healing. While it has been proposed to provide exogenousgrowth factors to the wound to help in this transition, there has been very little success using such an approachin practice. Peptide growth factors are rapidly degraded due to the overabundance of proteases in suchwounds. Furthermore, recent evidence suggests that the increased levels of advanced glycation endproducts(AGEs) in the diabetic environment may interfere with signaling pathways thus making target cells poorlyresponsive to bioactive peptides (such as growth factors and chemokines). We have recently shown that theseresponses can be restored by blocking the receptor to AGEs (RAGE) using soluble RAGE (sRAGE). Wepropose to develop a multi-functional nanoparticle system consisting of fusion proteins of elastin-like peptides(ELPs) with relevant bioactive peptides and sRAGE. We hypothesize that these nanoparticles can excludeproteases, protecting the attached biopeptides from degradation, and that the simultaneous release of sRAGEcan restore signaling in the diabetic wound. Furthermore, these nanoparticles spontaneously and reversiblyself-assemble at physiological temperatures, thus enabling rapid and inexpensive purification of the fusionproteins, and with a size below 1 micrometer, nanoparticles are small enough to be easily incorporated intotopical treatment modalities, including advanced methods (e.g. skin substitutes, which typically have pore sizesin excess of 50 micrometers). To test the hypothesis, we will develop a sRAGE-ELP fusion protein andcombine it with one of three different bioactive peptides that target different aspects of the wound healingprocess: KGF-ELP (epidermis), SDF-ELP (dermis), and ARA290-ELP (tissue protective response). Ourspecific aims are: (1) To develop sRAGE-ELP fusion proteins that reversibly form nanoparticles withthemselves and other peptide-ELP fusion proteins. (2) To evaluate the biological activity of ELP-basednanoparticles in a simulated diabetic environment in vitro. (3) To test the effect of sRAGE-ELP nanoparticles inin vivo diabetic wound conditions.
|Effective start/end date||7/15/16 → 4/30/18|
- National Institutes of Health (NIH)
Wounds and Injuries
Intercellular Signaling Peptides and Proteins
Negative-Pressure Wound Therapy