Re-epithelialization of Skin Wounds

皮肤伤口的上皮再生

• 批准号: 9339516
• 负责人: DAVID T. WOODLEY
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339516
• 关键词: Acute; Adult; Animals; Applications Grants; Basement membrane; Becaplermin; Biological; Biopsy; Bypass; Cell Culture Techniques; Cell Proliferation; Cells; Cicatrix; Clinic; Clinical Trials; Cutis Laxa; Data; Decubitus ulcer; Defect; Dermal; Diabetes Mellitus; Diabetic mouse; Diabetic wound; Disease; Drug Kinetics; Elderly; Endothelial Cells; Environment; Essential Drugs; Exhibits; Experimental Models; Family suidae; Fibroblasts; Fibrosis; Funding; Gel; Goals; Grant; Granulation Tissue; Growth Factor; Health; Health Care Costs; Heat shock proteins; Hepatotoxicity; Histology; Human; Hyperglycemia; Hypoxia; Hypoxia Inducible Factor; Impaired wound healing; In Vitro; Injection of therapeutic agent; Investigational New Drug Application; Laboratories; Lateral; Leg Ulcer; Lesion; Lower Extremity; Microscopic; Modeling; Mus; Myofibroblast; New Agents; Patients; Peptides; Pharmaceutical Preparations; Physiological; Platelet-Derived Growth Factor; Population; Preparation; Property; Proteins; Publishing; Recombinants; Reporting; Research; Skin; Skin wound; Streptozocin; Supplementation; Testing; Therapeutic; Time; Topical application; Translations; Vascularization; Veterans; Wound Healing; base; cell motility; chronic wound; diabetic; diabetic patient; diabetic wound healing; drug development; efficacy testing; extracellular; healing; human migration; in vivo; keratinocyte; liver metabolism; migration; neovascularization; non-diabetic; patient population; pre-clinical; protein metabolism; public health relevance; regenerative; wound closure

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.

描述（由申请人提供）： 糖尿病患者群体中的慢性皮肤伤口是国家和退伍军人管理局的一个主要健康问题。只有一种生物制剂 PDGF-BB（becaplermin 凝胶）获得美国联邦药物管理局 (FDA) 批准用于治疗糖尿病下肢皮肤伤口。然而，该产品的功效有限且费用昂贵限制了其在临床中的使用。在上一个 VA 资助周期中，我们确定了细胞外形式的热休克蛋白 90α (Hsp90�) 作为一种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（参与皮肤伤口愈合的细胞）细胞迁移的试剂。此外，当局部添加到正常和糖尿病小鼠的皮肤伤口中时，Hsp90�（及其较小的 F-5 片段）可显着加速伤口闭合。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（用于无血管化）的迁移来加速皮肤伤口的闭合。没有任何一种传统的生长因子能够起到同样的作用。在本提案中，我们希望测试重组 Hsp90� 和 F-5 在正常猪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、愈合伤口的疤痕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，并确定局部施用 Hsp90� 如何挽救糖尿病皮肤伤口的基本生物扰动，正如我们之前在 db/db 小鼠中报道的那样。通过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药物，以准备向 FDA 和人体临床试验申请研究性新药 (IND)。