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.

抽象的尽管存在多种治疗慢性糖尿病伤口的治疗选择，包括封闭敷料、真空辅助闭合、皮肤移植、生物工程皮肤替代品，在许多情况下，伤口无法愈合对治疗有充分的反应。慢性伤口的特点是无法从原伤口进展炎症至伤口愈合的增殖期。虽然有人建议提供外源性将生长因子添加到伤口中以帮助实现这一转变，但使用这种方法几乎没有成功在实践中。由于这些肽中的蛋白酶过多，肽生长因子会迅速降解。伤口。此外，最近的证据表明晚期糖基化终产物水平增加糖尿病环境中的 AGEs 可能会干扰信号通路，从而使靶细胞功能不佳对生物活性肽（例如生长因子和趋化因子）有反应。我们最近表明，这些使用可溶性 RAGE (sRAGE) 阻断 AGE (RAGE) 受体即可恢复反应。我们提议开发一种由类弹性蛋白肽融合蛋白组成的多功能纳米颗粒系统（ELP）与相关生物活性肽和 sRAGE。我们假设这些纳米粒子可以排除蛋白酶，保护附着的生物肽免遭降解，同时释放 sRAGE 可以恢复糖尿病伤口的信号传导。此外，这些纳米颗粒自发且可逆地在生理温度下自组装，从而能够快速且廉价地纯化融合体纳米颗粒的尺寸小于 1 微米，足够小，可以轻松融入蛋白质中局部治疗方式，包括先进方法（例如皮肤替代品，通常具有孔径大小）超过50微米）。为了验证这一假设，我们将开发一种 sRAGE-ELP 融合蛋白并将其与针对伤口愈合不同方面的三种不同生物活性肽之一相结合过程：KGF-ELP（表皮）、SDF-ELP（真皮）和 ARA290-ELP（组织保护反应）。我们的具体目标是：（1）开发可逆地形成纳米颗粒的 sRAGE-ELP 融合蛋白本身和其他肽-ELP 融合蛋白。 (2) 评价基于ELP的生物活性体外模拟糖尿病环境中的纳米颗粒。 (3) 测试sRAGE-ELP纳米粒子在体内糖尿病伤口状况。