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Protease Resistant growth factor formulations for chronic wound healing

用于慢性伤口愈合的蛋白酶抗性生长因子制剂

基本信息

批准号：
9310387
负责人：
Piyush Koria
金额：
$ 18.71万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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：
2016-07-05 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9310387
关键词：
Adult Affect Amputation Animal Model Animals Biological Caring Cavia Chimeric Proteins Clinic Clinical Data Decubitus ulcer Development Diabetes Mellitus Diabetic Foot Ulcer E protein Elastin Elderly Ensure Environment Family suidae Formulation Goals Growth Factor Hamsters Human Individual Injury Intervention Leg Leg Ulcer Light Liquid substance Modeling Mus Obesity Outcome Pathway interactions Patients Peptide Hydrolases Peptides Persons Population Property Protease Inhibitor Proteins Public Health Rattus Recombinant Growth Factor Recombinants Research Research Personnel Resistance Site Spinal cord injury Surgical Flaps System Testing Translations Venous Work Wound Healing base biomaterial compatibility chronic wound cost diabetic economic impact foot healing improved in vivo innovation loss of function nanoparticle non-healing wounds novel novel therapeutics pre-clinical therapeutic protein wound

项目摘要

PROJECT SUMMARY Chronic wounds such as venous leg ulcers (VLU), pressure sores and diabetic foot ulcers are challenging clinical problems that affect a growing number of people due to the global expansion of the elderly, diabetic and obese. VLU affect approximately 1% of the adult US population, i.e., 2.3 million individuals. There are approximately 1 million pressure ulcers per year in US with greatest impact on the elderly and spinal cord injured persons. Moreover, about 12 million individuals have diabetes mellitus in the US and it is expected that 25 % of these people will develop leg or foot problems. These wounds are difficult to treat and often drastic operative interventions such as amputations or free flaps with clear loss of function are necessary. The long term goals of this application are to develop novel therapies for healing of chronic wounds resulting because of diabetes or some other circulatory condition. Researchers have shown for years that proteins called growth factors improve the healing of chronic wounds, but their use in clinics is limited. This is commonly attributed to the delivery of soluble growth factors to the injury site which is expensive and challenging. However, animal models also lack the harsh protease rich environment present in human chronic wounds. The impact of this environment on growth factor delivery systems has not been examined. We hypothesize that it is the critical barrier to the successful translation of GF therapies to human patients. Here, we describe an innovative two pronged strategy to overcome this barrier. First, we propose to develop multifunctional nanoparticles (mNPs) comprised of GFs and protease inhibitor peptides (PIP) fused to elastin-like-peptide (ELPs). Elastin-like-peptides (ELPs) are attractive carriers owing to their biocompatibility and unique self- assembling properties. Recently, we have shown that chimeric fusion of GF and ELPs self-assembles into NPs without loss of biological activity of the GF. Based on this finding we hypothesize that addition of PIP-ELP to GF-ELP fusion protein will form mNPs that not only effectively deliver the GF but also protect it from proteolytic degradation. This mNP formulation will improve chronic wound healing outcomes over simply mixing the ingredients by ensuring the proximity of PIP with the GF. Second, we propose a novel animal wound model that has protease levels similar to human chronic wounds. We have preliminary data that correlates high protease activity with non-healing wounds in mice. We propose to use this model to test the ability of mNPs to heal the wounds. Successful completion of the project will result in protease resistant growth factor formulations that will induce healing in a proteolytic environment similar to human chronic wounds. Also, this research will shed light on the importance of proteases in wound healing and how excessive protease activity leads to a chronic wound. This approach can be easily extended to incorporate any growth factor and any protease inhibitor thereby broadening its scope beyond healing of chronic skin wounds.

项目摘要慢性伤口，如下肢静脉溃疡（VLU）、压疮和糖尿病足溃疡，由于老年人、糖尿病患者和老年人的全球扩张，肥胖VLU影响大约1%的美国成年人口，即，2.3百万人。有美国每年约有100万例压疮，对老年人和脊髓的影响最大受伤的人。此外，在美国约有1200万人患有糖尿病，预计 25%的人会出现腿或脚的问题。这些伤口很难治疗，而且往往很严重手术干预，如截肢或游离皮瓣与明确的功能丧失是必要的。本申请的长期目标是开发用于慢性伤口愈合的新疗法，因为糖尿病或其他循环系统疾病多年来研究人员已经证明，所谓的生长因子可以促进慢性伤口的愈合，但它们在临床上的应用有限。这通常被这归因于将可溶性生长因子递送至损伤部位，这是昂贵且具有挑战性的。然而，动物模型也缺乏人类慢性伤口中存在的苛刻的富含蛋白酶的环境。的这种环境对生长因子递送系统的影响尚未被研究。我们假设它是这是将GF疗法成功转化为人类患者的关键障碍。在这里，我们描述了一个创新的双管齐下的战略，以克服这一障碍。首先，我们建议开发多功能由融合到弹性蛋白样肽的GF和蛋白酶抑制剂肽（PIP）组成的纳米颗粒（mNP （ELP）。弹性蛋白样肽（Elastin-like-peptides，ELP）是一种具有生物相容性和独特的自组装特性的新型载体。组装性能。最近，我们发现GF和ELP的嵌合融合物自组装成NP 而不损失GF的生物活性。基于这一发现，我们假设将PIP-ELP添加到 GF-ELP融合蛋白将形成mNPs，其不仅有效地递送GF，而且还保护其免受蛋白水解降解这种mNP制剂将改善慢性伤口愈合结果，而不是简单地混合通过确保PIP与GF的接近来控制配料。其次，我们提出了一种新的动物创伤模型，其蛋白酶水平与人类慢性伤口相似。我们有初步数据显示蛋白酶活性与小鼠的不愈合伤口。我们建议使用这个模型来测试mNP的能力，治愈伤口该项目的成功完成将导致蛋白酶抗性生长因子制剂，在类似于人类慢性伤口的蛋白水解环境中愈合。此外，这项研究将阐明蛋白酶在伤口愈合中的重要性以及过度的蛋白酶活性如何导致慢性伤口。这该方法可以容易地扩展到掺入任何生长因子和任何蛋白酶抑制剂，将其范围扩大到慢性皮肤伤口的愈合之外。