Therapeutic Role of Inter-alpha Inhibitors in Wound Healing

Inter-α 抑制剂在伤口愈合中的治疗作用

• 批准号: 8834088
• 负责人: YOW-PIN LIM
• 金额: $ 22.47万
• 依托单位: PROTHERA BIOLOGICS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-17 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8834088
• 关键词: Accounting; Acute; Admission activity; Affect; Amputation; Animals; Anthrax disease; Binding; Biological Availability; Biological Products; Blood; CD44 gene; Carboxymethylcellulose; Caring; Chronic; Cicatrix; Clinical; Clinical Management; Complex; Complication; Cytoskeleton; Data; Debridement; Development; Diabetic mouse; Diabetic ulcer; Diabetic wound; Disease; Drug Formulations; Due Process; Elastases; Ethylene Glycols; Experimental Models; Extracellular Matrix; Family; Fibronectins; Gel; Glycosaminoglycans; Goals; Healed; Hospitalization; Human; Hyaluronan; Immune response; Immunomodulators; Impaired wound healing; In Vitro; Infection; Infection Control; Inflammation; Inflammatory; Injury; Intervention; Intoxication; Investigation; Kinetics; Knockout Mice; Legal patent; Lesion; Life; Light; Link; Literature; Local Therapy; Lower Extremity; Modeling; Mus; Natural regeneration; Pain; Phase; Plasma; Plasma Proteins; Plasmin; Play; Preclinical Testing; Process; Protease Inhibitor; Proteins; Public Health; Replacement Therapy; Research; Role; Sepsis; Sepsis Syndrome; Serine Protease; Shock; Skin; Small Business Innovation Research Grant; Source; Sterile coverings; Surface; Syndrome; Tenascin; Testing; Therapeutic; Thick; Tissues; Topical application; Translating; Trypsin; Vitronectin; Weight-Bearing state; Work; Wound Healing; angiogenesis; base; bikunin; biodefense; bioprocess; cell type; clinical care; crosslink; design; diabetic; diabetic patient; efficacy testing; ethylene glycol; fighting; healing; improved; in vivo; inter-alpha-inhibitor; mouse model; non-diabetic; novel; novel therapeutics; open wound; polypeptide; prevent; product development; public health relevance; receptor; research and development; standard of care; treatment effect; wound

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.

描述(由申请人提供)：伤口愈合是一个复杂的调节过程，大致以炎症、增殖和重塑阶段为特征。这些阶段中的任何一个阶段的失衡都可能导致愈合不充分、疤痕形成，或者导致慢性伤口的发展，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。这些慢性伤口使人虚弱、疼痛，而且往往永远不会完全愈合。尽管进行了广泛的研究和产品开发来改善伤口护理，但这些损伤的临床护理标准几十年来基本上没有变化。间α抑制蛋白(IAIP)是一种天然衍生的分子，在调节宿主对病理性侮辱的反应时，它是人体保护防御的重要组成部分。目前，这些蛋白正被开发为一种有效的治疗方法，用于治疗急性威胁生命的疾病，如全身炎症反应综合征(SIRS)、脓毒症和炭疽中毒以及在生物防御应用中的感染。IAIP不仅在炎症和血管生成中发挥重要作用，而且在伤口愈合过程中也发挥重要作用。我们最近使用IAIP缺陷的转基因小鼠(bikunin基因敲除小鼠)进行的研究发现，由于细胞外基质(ECM)重组的中断，伤口修复过程失调。此外，我们发现糖尿病小鼠伤口组织中IAIP水平明显低于非糖尿病对照组，提示糖尿病小鼠伤口组织中IAIP受损和耗竭。IAIP由多个亚基(重的和轻的)链组成，这些链由糖胺聚糖唯一地连接在一起。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体，使其能够有效地与其受体(如CD44)结合。IAIP重链也已知与基质细胞蛋白相互作用，如玻璃连蛋白、纤维连接蛋白和Tenascin c，以促进伤口愈合。在这项建议中，我们希望开发一种新的局部IAIP配方，并在三种不同的创面愈合实验模型中，使用IAIP缺陷(KO)、单基因糖尿病和多基因Tallyho糖尿病小鼠，获得局部IAIP治疗方法的有效性的概念证明。我们假设IAIP将在影响表皮再生和细胞外基质组织的伤口愈合过程中发挥重要作用。如果得到证实，这种基于血浆来源的IAIP的新型局部治疗方法可以很容易地转化为临床使用，用于有问题的和慢性的伤口护理。局部免疫调节性IAIP治疗也可以预防伤口并发症和双重感染，这使得本研究的潜在影响是巨大的。