A Targeted Approach to Managing Salivary Gland Inflammation Using Resolvins

使用 Resolvins 治疗唾液腺炎症的有针对性的方法

• 批准号: 10250559
• 负责人: Olga Juliana Baker
• 金额: $ 36.87万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-10 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250559
• 关键词: Address; Area; Aspirin; Autoantibodies; Autoimmune Diseases; Biopsy; Blood; Blood Circulation; CD59 Antigen; Cell Culture Techniques; Cell Survival; Cells; Chronic; Coupled; Cytokine Signaling; Destinations; Development; Diagnostic; Diffuse; Diffusion; Disease; Dopamine D1 Receptor; Dose; Dryness; Eicosanoids; FPR2 gene; Face; Family; Functional disorder; Future; GTP-Binding Proteins; Goals; Half-Life; Human; Infection; Infiltration; Inflammation; Inflammatory; Injury; Investigation; Knock-in Mouse; Knockout Mice; Lead; Light; Lipids; Lymphocyte; Mediating; Mediator of activation protein; Methods; Minor salivary gland structure; Mus; Oral cavity; Oral health; Oxidoreductase; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Process; Production; Property; Quality of life; Recovery; Recurrence; Resolution; Saliva; Salivary; Salivary Glands; Salivary duct structure; Sialadenitis; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Stream; Submandibular gland; System; Therapeutic; Time; Tissues; Translating; Woman; Xerostomia; base; clinical application; cytokine; effective therapy; human disease; improved; mouse model; novel; optimal treatments; preservation; receptor; response; saliva secretion; salivary cell; targeted delivery; translational study

ABSTRACT Sjögren's syndrome (SS) is an autoimmune disease characterized by chronic inflammation and diminished secretory function of the salivary glands (SG). Diagnostic features include dry mouth, lymphocytic infiltration into the SG and presence of antinuclear autoantibodies in plasma. SS greatly decreases the patient’s quality of life, and although extensive investigation has been done to understand it, causes of and effective treatments for the disease are still unknown. In light of the high degree of need and the limitations of current therapies, development of novel treatments to decrease inflammation and restore SG secretory function is essential. Our previous studies demonstrated that SG express the AT-RvD1 receptor ALX/FPR2 to block pro-inflammatory cytokine signaling, thereby promoting cell survival and tissue integrity in SS. More recently, we demonstrated that AT-RvD1 treatment in SS-like NOD/ShiLtJ mice fully preserves secretory functioning, downregulates pro- inflammatory cytokine expression and promotes pro-resolving signaling pathways. Encouraging as these results may be, however, lymphocytic infiltration persists in AT-RvD1 treated SS mice, raising the possibility of future pro-inflammatory cytokine production and possible recurrence of hypofunction. Moreover, we face issues related to the properties of resolvins themselves that must be overcome for clinical applications to be achieved. Specifically, a significant portion of administered resolvins (RvD1 included) do not reach their intended destination with the desired regularity because they are quickly inactivated by eicosanoid oxidoreductases (EOR) and their effects can be diffusely distributed throughout the body. Furthermore, the problem of instability extends to the AT forms, which are somewhat less susceptible to inactivation. In addition to these issues of durability, resolvins are relatively expensive, and when taken together, these concerns raise questions about the feasibility of any treatment requiring large doses to be introduced into the blood stream. In response, we believe that all of these issues may be addressed by infusing AT-RvD1 retrograde to the salivary ducts, which could allow the benefits demonstrated by AT-RvD1 (i.e., preserved and/or restored saliva secretion) to be retained while addressing areas of weakness discussed earlier. Moreover, to better exploit the use of AT-RvD1, we will study the mechanisms by which it activates the ALX/FPR2 using a knock-out mouse for this receptor (ALX/FPR2-/-). Next, we will describe the ALX/FPR2 signaling mechanisms in mouse and human cells. Finally, we will determine whether ALX/FPR2 signaling pathways are altered in minor SG biopsies (both with and without SS), thereby further extending our findings to the human disease. Our overall hypothesis is that healthy SG functioning will be restored by local AT-RvD1 treatment. Aim 1 will demonstrate the benefits of delivering AT-RvD1 locally for restoring SG function. Aim 2 will determine ALX/FPR2 signaling mechanisms and Aim 3 will translate ALX/FPR2 signaling mechanisms to humans.

摘要 舍格伦综合征（SS）是一种自身免疫性疾病，其特征是慢性炎症和免疫功能减退。 唾液腺（SG）的分泌功能。诊断特征包括口干，淋巴细胞浸润 以及血浆中抗核自身抗体的存在。SS大大降低了患者的生活质量。 生活，虽然已经做了广泛的调查，以了解它，原因和有效的治疗 这种疾病仍然未知。鉴于高度的需求和目前治疗的局限性， 开发新的治疗方法以减少炎症和恢复SG分泌功能是必要的。我们 以往的研究表明，SG表达AT-RvD 1受体ALX/FPR 2，以阻断促炎性反应， 细胞因子信号传导，从而促进SS中的细胞存活和组织完整性。最近，我们证明了 在SS样NOD/ShiLtJ小鼠中，AT-RvD 1治疗完全保留了分泌功能，下调了促分泌功能， 炎性细胞因子表达和促进促消退信号传导途径。令人鼓舞的是， 然而，结果可能是，在AT-RvD 1处理的SS小鼠中淋巴细胞浸润持续存在，增加了 未来促炎细胞因子的产生和功能减退的可能复发。此外，我们面临 与消退素本身的性质有关的问题， 办妥了一批具体而言，很大一部分给药的消退素（包括RvD 1）没有达到其 因为它们很快被类花生酸灭活， 氧化还原酶（EOR）及其作用可扩散分布于全身。而且 不稳定性的问题延伸到AT形式，其对失活的敏感性稍低。此外 对于这些耐久性问题，解决方案相对昂贵， 任何需要大剂量引入血流的治疗的可行性问题。在 我们认为，所有这些问题都可以通过将AT-RvD 1逆行注入唾液来解决。 导管，这可以允许AT-RvD 1所展示的益处（即，保存和/或恢复的唾液 分泌），同时解决前面讨论的薄弱领域。此外，为了更好地利用 使用AT-RvD 1，我们将使用基因敲除小鼠研究其激活ALX/FPR 2的机制 该受体（ALX/FPR 2-/-）。接下来，我们将描述小鼠中ALX/FPR 2信号传导机制， 人类细胞。最后，我们将确定ALX/FPR 2信号通路是否在轻微SG中改变， 活组织检查（有和没有SS），从而进一步将我们的发现扩展到人类疾病。我们的整体 假设健康SG功能将通过局部AT-RvD 1治疗恢复。目标1将展示 在本地输送AT-RvD 1以恢复SG功能的好处。目标2将确定ALX/FPR 2信号传导 机制和Aim 3将把ALX/FPR 2信号机制翻译给人类。