Therapeutic Role of Inter-alpha Inhibitors in Wound Healing

描述（由申请人提供）：伤口愈合是一个复杂的调节过程，其广泛特征在于炎症、增殖和重塑阶段。这些阶段中任何一个的不平衡都可能导致愈合不充分、疤痕形成或慢性伤口的发展，如糖尿病溃疡。糖尿病溃疡是世界上大多数下肢截肢的原因，也是糖尿病患者住院的主要原因之一。这些慢性伤口使人衰弱、疼痛，并且经常无法完全愈合。尽管进行了广泛的研究和产品开发以改善伤口护理，但数十年来这些病变的临床护理标准基本上没有变化。间-α抑制蛋白（IAIP）是天然衍生的分子，其在调节宿主对病理性损伤的反应中充当身体保护性防御的关键组分。目前，这些蛋白质正在被开发为治疗急性危及生命的疾病的有效疗法，例如全身炎症反应综合征（SIRS）、脓毒症和炭疽中毒以及生物防御应用中的感染。IAIP不仅在炎症和血管生成中起重要作用，而且在伤口愈合过程中也起重要作用。 我们最近使用IAIP缺陷的遗传改变小鼠（bikunin敲除小鼠）的研究揭示了由于细胞外基质（ECM）重组的破坏而导致的失调的伤口修复过程。此外，我们发现，与非糖尿病对照相比，糖尿病小鼠伤口组织中的IAIP水平显著降低，表明糖尿病伤口中的IAIP受损和耗尽。IAIP由多个亚基（重链和轻链）链组成，这些亚基链通过糖胺聚糖独特地连接。虽然IAIP轻链（也称为bikunin）抑制各种丝氨酸蛋白酶，但IAIP的重链与透明质酸形成共价复合物，以允许有效结合其受体（如CD 44）。还已知IAIP重链与基质细胞蛋白如玻连蛋白、纤连蛋白和腱生蛋白c相互作用以促进伤口愈合。 在该提案中，我们希望开发一种新的局部IAIP制剂，并在使用IAIP缺陷（KO）、单基因糖尿病和多基因TallyHo糖尿病小鼠的三种不同的伤口愈合实验模型中获得局部IAIP治疗方法的功效的概念验证。我们假设IAIP将在伤口愈合过程中发挥重要作用，影响表皮再生以及细胞外基质组织。如果得到证实，这种基于血浆衍生的IAIP的新型局部治疗可以容易地转化为临床应用，用于有问题的和慢性的伤口护理。局部免疫调节IAIP治疗还可以预防伤口并发症和超级感染，这使得这项研究的潜在影响巨大。

DESCRIPTION (provided by applicant): Wound healing is an intricately regulated process broadly characterized by phases of inflammation, proliferation, and remodeling. Imbalances in any one of these phases can result in inadequate healing, scar formation, or in the development of chronic wounds, such as diabetic ulcers. Diabetic ulcers are responsible for the majority of lower extremity amputations in the world and are among the principal reasons for hospitalization of diabetic patients. These chronic wounds are debilitating, painful, and frequently never completely heal. Despite extensive research and product development to improve wound care, the clinical standard of care for these lesions has been largely unchanged for decades. Inter-alpha Inhibitor Proteins (IAIP) are naturally derived molecules that serve as a crucial component of the body's protective defenses in modulating host response to pathological insults. Currently, these proteins are being developed as a potent therapy to treat acute life threatening diseases such as systemic inflammatory response syndrome (SIRS), sepsis and Anthrax intoxication and infection in biodefense applications. IAIP have been described to play an important role not only in inflammation and angiogenesis but also in the wound healing process. Our recent investigations using genetically altered mice deficient in IAIP (bikunin knockout mice) revealed a dysregulated wound repair process due to disruption of extracellular matrix (ECM) reorganization. Additionally, we found that IAIP level is markedly decreased in the wound tissues of diabetic mice compared to non-diabetic controls suggesting impaired and depleted IAIP in the diabetic wound. IAIP consist of multiple subunit (heavy and light) chains uniquely linked by glycosaminoglycan. While the IAIP light chain (also called bikunin) inhibits various serine proteases, the heavy chains of IAIP form covalent complexes with hyaluronan to allow efficient binding to its receptors (such as CD44). The IAIP heavy chains also known to interact with matrix cellular proteins such as vitronectin, fibronectin and tenascin c to promote wound healing. In this proposal we would like to develop a novel topical IAIP formulation and obtain proof-of-concept of efficacy of a localized IAIP treatment approach in three different experimental models of wound healing using IAIP-deficient (KO), monogenetic diabetic and polygenetic TallyHo diabetic mice. We hypothesize that IAIP will play a significant role in the wound healing process affecting epidermal regeneration as well as extracellular matrix organization. If confirmed, this novel topical treatment based on plasma derived IAIP can be translated readily into the clinical use for problematic and chronic wound care. The localized immunomodulatory IAIP treatment might also prevent wound complication and super infection making the potential impact of this research immense.