Re-epithelialization of Skin Wounds

描述（由申请人提供）： 糖尿病患者群体的慢性皮肤伤口是国家和退伍军人事务部的一个主要健康问题。只有一种生物制剂PDGF-BB（贝卡普勒明凝胶）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，该产品的适度功效和费用限制了其在临床中的使用。在上一个VA补助周期中，我们已经确定了热休克蛋白90 α（Hsp 90 <$）的细胞外形式作为促进人类角质形成细胞，人类真皮成纤维细胞和人类微血管内皮细胞迁移的试剂，这些细胞参与皮肤伤口愈合。此外，Hsp 90当局部添加到正常和糖尿病小鼠的皮肤伤口上时，其F-5片段（及其较小的F-5片段）显著加速伤口闭合。我们的假设是，热休克蛋白90通过促进角质形成细胞（用于上皮再生）、真皮成纤维细胞（用于纤维增生）和微血管内皮细胞（用于无血管形成）的迁移来加速皮肤伤口的闭合。没有一种传统的生长因子能够做到这一点。在这项提议中，我们希望测试重组Hsp 90和F-5在正常和糖尿病猪中加速伤口闭合的功效，这些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、愈合伤口的瘢痕形成质量和任何程度的“再生”（而非“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，并确定局部给药的Hsp 90是如何拯救糖尿病皮肤伤口中的基本生物扰动的，正如我们以前在db/db小鼠中报道的那样。有了这些机制研究与我们的猪体内伤口愈合数据相结合，我们将准备推进这种潜在的药物，用于向FDA和人体临床试验申请研究性新药（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.