Re-epithelialization of Skin Wounds

描述(由申请人提供)： 糖尿病患者群体中的慢性皮肤创伤是国家和退伍军人管理局的主要健康问题。只有一种生物，PDGF-BB(倍卡普明凝胶)，被联邦药物管理局(FDA)批准用于治疗糖尿病下肢皮肤伤口。然而，该产品有限的疗效和昂贵的费用限制了其在临床上的使用。在上一次VA赠款周期中，我们已经确定细胞外形式的热休克蛋白90α(Hsp90？)是一种促进人角质形成细胞、人真皮成纤维细胞和人微血管内皮细胞的细胞迁移的试剂，而这些细胞正是参与皮肤伤口愈合的细胞。此外，当将Hsp90？(及其较小的F-5碎片)局部添加到正常和糖尿病小鼠的皮肤伤口时，显著加速了伤口的愈合。我们的假设是，Hsp90通过促进角质形成细胞(用于再上皮化)、真皮成纤维细胞(用于纤维增生)和微血管内皮细胞(用于非血管化)的迁移来加速皮肤伤口的愈合。没有一个单一的传统增长因素能够做到这一点。在这项建议中，我们希望测试重组Hsp90和F-5在正常和糖尿病猪身上加速伤口闭合的效果，这两种动物的皮肤在生物学上最接近人类皮肤。我们将评估伤口闭合率、愈合伤口的质量，以及任何程度的“再生”(而不是“修复”)伤口愈合。其次，我们将探索糖尿病抑制皮肤伤口闭合的机制，并确定局部应用Hsp90如何拯救糖尿病皮肤伤口的基本生物扰动，正如我们之前在db/db小鼠中所报道的那样。随着这些机理研究与我们的猪体内伤口愈合数据相结合，我们将准备将这种潜在的制剂用于FDA和人类临床试验的研究性新药(IND)。

DESCRIPTION (provided by applicant): Chronic skin wounds in the diabetic patient population are a major health problem for the Nation and the VA. Only one biologic, PDGF-BB (becaplermin Gel), is approved by the Federal Drug Administration (FDA) to treat diabetic lower limb skin wounds. However, the modest efficacy and expense of this product have limited its use in the clinic. During the last VA grant cycle, we have identified the extracellular form of heat shock protein 90alpha (Hsp90¿) as an agent that promotes the cellular migration of human keratinocytes, human dermal fibroblasts and human microvascular endothelial cells, the very cells involved in skin wound healing. Moreover, Hsp90¿ (and its smaller F-5 fragment) when added topically to skin wounds of normal and diabetic mice dramatically accelerates the wound closure. Our hypothesis is that Hsp90¿ accelerates the closure of skin wounds by promoting migration of keratinocytes (for re-epithelialization), dermal fibroblasts (for fibroplasia) and microvascular endothelial cells (for no-vascularization). No single conventional growth factor is able to do the same. In this proposal, we wish to test the efficacy of recombinant Hsp90¿ and F-5 to accelerate wound closure in normal and diabetic pigs, the animal species whose skin is biologically the closest to human skin. We will evaluate the rate of wound closure, the quality of the healed wounds with regard to scarring and any degree of "regenerative" (rather than "reparative") wound healing. Secondly, we will explore the mechanisms by which diabetes inhibits the closure of skin wounds and determine how topically administered Hsp90¿ rescues the basic biological perturbation in diabetic skin wounds, as we previously reported in db/db mice. With these mechanistic studies paired with our porcine in vivo wound healing data, we will be poised to advance this potential agent for preparation of an investigational new drug (IND) application to the FDA and human clinical trials.