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Multifunctional Nanoparticles Containing sRAGE Potentiated Bioactive Peptides for Wound Healing

含有 sRAGE 增强生物活性肽的多功能纳米粒子，用于伤口愈合

基本信息

批准号：
9310393
负责人：
Francois Berthiaume
金额：
$ 23.4万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9310393
关键词：
Address Advanced Glycosylation End Products Binding Biological Biomedical Engineering Cell Culture Techniques Cell Proliferation Cells Chimeric Proteins Chronic Clinical Complications of Diabetes Mellitus Dermal Dermis Diabetic mouse Diabetic wound Elastin Environment Epidermis Excision FDA approved Failure Gelatinase B Generations Glucose Growth Factor Healthcare Systems Human Impaired wound healing Impairment In Vitro Infection Inflammatory Injury Light Lipids Liquid substance Lower Extremity Medicare/Medicaid Methods Modality Modeling Morbidity - disease rate Occlusive Dressings Pathway interactions Peptide Hydrolases Peptides Performance Phase Physiological Process Production Proteins Proteolysis Reactive Oxygen Species Reporting Research Signal Pathway Signal Transduction Skin Skin Substitutes Skin graft Skin wound Stress System Temperature Testing Therapeutic Tissue Engineering Tissues Topical application Transcriptional Activation Vacuum Wound Healing base cell motility chemokine chronic wound cost design diabetic diabetic wound healing healing improved in vivo in vivo regeneration keratinocyte growth factor limb amputation nanoparticle non-healing wounds novel novel therapeutics peptide drug prevent protein B receptor receptor for advanced glycation endproducts response self assembly success sugar transcription factor wound

项目摘要

ABSTRACT 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 to adequately 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 exogenous growth factors to the wound to help in this transition, there has been very little success using such an approach in practice. Peptide growth factors are rapidly degraded due to the overabundance of proteases in such wounds. 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 poorly responsive to bioactive peptides (such as growth factors and chemokines). We have recently shown that these responses can be restored by blocking the receptor to AGEs (RAGE) using soluble RAGE (sRAGE). We propose 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 exclude proteases, protecting the attached biopeptides from degradation, and that the simultaneous release of sRAGE can restore signaling in the diabetic wound. Furthermore, these nanoparticles spontaneously and reversibly self-assemble at physiological temperatures, thus enabling rapid and inexpensive purification of the fusion proteins, and with a size below 1 micrometer, nanoparticles are small enough to be easily incorporated into topical treatment modalities, including advanced methods (e.g. skin substitutes, which typically have pore sizes in excess of 50 micrometers). To test the hypothesis, we will develop a sRAGE-ELP fusion protein and combine it with one of three different bioactive peptides that target different aspects of the wound healing process: KGF-ELP (epidermis), SDF-ELP (dermis), and ARA290-ELP (tissue protective response). Our specific aims are: (1) To develop sRAGE-ELP fusion proteins that reversibly form nanoparticles with themselves and other peptide-ELP fusion proteins. (2) To evaluate the biological activity of ELP-based nanoparticles in a simulated diabetic environment in vitro. (3) To test the effect of sRAGE-ELP nanoparticles in in vivo diabetic wound conditions.

摘要