RESOLUTION OF CYTOKINE-MEDIATED SALIVARY GLAND INFLAMMATION

细胞因子介导的唾液腺炎症的解决

• 批准号: 9507142
• 负责人: Olga Juliana Baker
• 金额: $ 37.92万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9507142
• 关键词: Acids; Address; Arachidonate 5-Lipoxygenase; Area; Aspirin; Autoantibodies; Autoimmune Diseases; Blood Vessels; Cell Survival; Cells; Chronic; Combined Modality Therapy; Coupled; Cytokine Signaling; Data; Destinations; Development; Dexamethasone; Diagnostic; Dimensions; Disease; Dryness; Eicosanoids; Eicosapentaenoic Acid; Elastin; Encapsulated; Engineering; Enzymes; Epithelial; Epithelium; Exocrine Glands; FPR2 gene; Face; Functional disorder; Funding; G-substrate; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Goals; Half-Life; Human; Immunologics; Impairment; Infection; Infiltration; Inflammation; Inflammatory; Injury; Intravenous; Investigation; Light; Lymphocyte; Mediating; Messenger RNA; Methods; Micelles; Minor salivary gland structure; Mus; Oral cavity; Oral health; Oxidoreductase; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Process; Production; Property; Proteins; Resolution; Saliva; Salivary; Salivary Glands; Series; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Symptoms; System; Therapeutic; Tissues; Translating; Woman; Xerostomia; alternative treatment; analog; biomaterial compatibility; clinical application; cytokine; effective therapy; functional restoration; in vivo; lipid mediator; mRNA Expression; mouse model; nanoparticle; novel therapeutic intervention; polypeptide; protein expression; receptor; response; salivary cell; targeted delivery

ABSTRACT Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disease characterized by diminished secretory function of the exocrine glands. Treatments for hyposalivation are limited to use of saliva substitutes and medications that provide only temporary relief. In light of the high degree of need and the limitations of current therapies, development of alternative treatments to restore functioning is essential. Resolvins (Rv), which are which are highly potent lipid mediators, offer a viable alternative for better treating inflammatory diseases such as SS. Results from our previous funding period demonstrated the following: a) salivary glands express the RvD1 and AT-RvD1 receptor (ALX/FPR2); b) activation of ALX/FPR2 blocks pro-inflammatory cytokine signaling, thereby promoting cell survival and tissue integrity in salivary cells; c) RvD1 biosynthetic pathways are functional in salivary epithelium; d) loss of ALX/FPR2 results in unresolved inflammation and SMG dysfunction in vivo; e) AT-RvD1 treatment in SS-like NOD/ShiLtJ mice fully preserves secretory functioning, downregulates pro-inflammatory cytokine expression and promotes pro-resolving signaling pathways; f) treatment combining AT-RvD1 and dexamethasone (DEX) reduces salivary gland lymphocytic infiltration in comparison to AT-RvD1 alone, g) a three-dimensional culture system using human SMG cells was optimized for the study of ALX/FPR2 signaling and h) human saliva was demonstrated to express resolvin lipid mediators. Promising though these findings may be, however, we face significant issues that must be overcome for the clinical application of resolvins to be achieved. Specifically, resolvins (RvD1 included) do not reach their intended destination with desired regularity because they are quickly inactivated by eicosanoid oxidoreductases or EORs upon introduction to the body, have a short plasma half-life (approximately 3 h) and have effects that are spread throughout the body (such that they cannot specifically target inflamed areas, as would be needed for optimal treatment of inflammatory diseases). Furthermore, the problem of instability extends to the AT forms, which are somewhat less susceptible to inactivation but still demonstrate less than ideal stability. However, we believe that all of these issues may be addressed by use of elastin-like polypeptide nanoparticles (iTEP NPs), which are biocompatible micelle-like molecules engineered to contain AT-RvD1. Specifically, iTEP NPs are capable of protecting AT-RvD1 from inactivation, increasing plasma half-life and easily permeating inflamed blood vessels, thereby allowing them to congregate in areas of inflammation. The main goal of this proposal is to determine whether SS symptoms can be reduced by AT-RvD1 treatment. Aim 1: will demonstrate the utility of AT-RvD1 treatment in the NOD/ShiLtJ SS mouse model. Aim 2: will translate AT-RvD1 treatment to human salivary cells and Aim 3: will enhance AT-RvD1 treatment through a delivery system using iTEP NPs.

摘要 舍格伦综合征（SS）是一种慢性炎症性自身免疫性疾病，其特征在于分泌性白细胞减少， 外分泌腺的功能。唾液过少的治疗仅限于使用唾液替代品， 药物只能提供暂时的缓解。鉴于高度的需求和目前的限制， 因此，开发替代疗法以恢复功能至关重要。Resolvins（Rv）， 它们是高效的脂质介质，为更好地治疗炎症性疾病提供了可行的替代方案， 作为SS。我们上一个资助期的结果表明：a）唾液腺表达 RvD 1和AT-RvD 1受体（ALX/FPR 2）; B）ALX/FPR 2的活化阻断促炎细胞因子 信号传导，从而促进唾液细胞中的细胞存活和组织完整性; c）RvD 1生物合成途径 d）ALX/FPR 2的缺失导致未解决的炎症和SMG 体内功能障碍; e）SS样NOD/ShiLtJ小鼠中的AT-RvD 1治疗完全保留了分泌功能， 下调促炎细胞因子表达并促进促消退信号传导途径; f） AT-RvD 1和地塞米松（DEX）联合治疗可减少唾液腺淋巴细胞浸润， 与单独的AT-RvD 1相比，g）优化使用人SMG细胞的三维培养系统 用于ALX/FPR 2信号传导的研究，并且h）人唾液被证明表达消退素脂质 调解员尽管这些发现可能是有希望的，但是，我们面临着必须解决的重大问题。 为消退素的临床应用所克服。具体而言，消退蛋白（包括RvD 1）不 以所需的规律性到达它们的预定目的地，因为它们被类花生酸迅速灭活 氧化还原酶或EOR在引入体内后具有短的血浆半衰期（约3小时）， 具有遍布全身的效果（使得它们不能特异性地针对发炎区域， 将需要用于炎性疾病的最佳治疗）。此外，不稳定性问题 延伸到AT形式，其对失活的敏感性稍低，但仍表现出低于 理想的稳定性然而，我们相信所有这些问题都可以通过使用弹性蛋白样多肽来解决。 纳米颗粒（iTEP NP），其是生物相容性胶束样分子，被工程化以包含AT-RvD 1。 具体地，iTEP NP能够保护AT-RvD 1免于失活，增加血浆半衰期， 容易渗透发炎的血管，从而使它们聚集在炎症区域。的 该提案的主要目的是确定AT-RvD 1治疗是否可以减轻SS症状。目的 1：将证明AT-RvD 1治疗在NOD/ShiLtJ SS小鼠模型中的效用。目标2：翻译 AT-RvD 1对人唾液细胞的治疗和Aim 3：将通过递送增强AT-RvD 1治疗 使用iTEP NP的系统。