Layilin as a modulator of platelet activation and thromboinflammation

Layilin 作为血小板活化和血栓炎症调节剂

• 批准号: 10607168
• 负责人: Rebecca Mellema
• 金额: $ 3.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607168
• 关键词: Adhesions; Affect; Antibodies; Automobile Driving; Binding; Biological Assay; Blood Platelets; CD44 Antigens; CD44 gene; Cause of Death; Cells; Characteristics; Chronic; Circulation; Colitis; Colon; Data; Disease; Disease Progression; Drug Targeting; Enzymes; Extracellular Matrix; F2R gene; Flow Cytometry; Foundations; Functional disorder; Gastrointestinal tract structure; General Population; Glycosaminoglycans; Goals; Human; Hyaluronan; Hyaluronidase; Hyperactivity; Immune; Immunosuppressive Agents; Impairment; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Innate Immune Response; Intestines; Knockout Mice; Leukocytes; Link; Measures; Mediating; Megakaryocytes; Metabolism; Mission; Molecular; Mus; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Platelet Activation; Platelet aggregation; Play; Public Health; Receptor Inhibition; Research; Risk; Role; Signal Transduction; Site; Structure; Submucosa; Surface; Symptoms; Testing; Thromboembolism; Thrombosis; Tissues; Ulcerative Colitis; Work; cell type; chronic inflammatory disease; cytokine; immune cell infiltrate; in vivo; innate immune mechanisms; innovation; insight; leukocyte activation; mortality; mouse model; murine colitis; new therapeutic target; novel; novel therapeutics; platelet function; prevent; receptor; receptor binding; recruit; thromboinflammation

Abstract Inflammatory Bowel Disease (IBD) is characterized by inappropriate immune cell infiltration within the colon and incidence of this disease grows annually. With currently no cure, patients can only mitigate symptoms through surgery and immunosuppressants. An extracellular matrix component, hyaluronan (HA), is synthesized into cable-like structures during inflammation that act as attachment sites for recruited leukocytes. Platelets bind to these cables and degrade the HA and this capability to metabolize HA is lost during IBD. These HA fragments have pro-inflammatory effects when released into circulation. How platelets recognize HA, however, is unknown. Our long-term goal is to determine a potential drug target for non-invasive treatment in IBD patients by targeting HA receptors on platelets. We have previously found that, contrary to what would be expected, the predominant HA receptor on platelets is not CD44, but the understudied receptor, layilin. The objective of this proposal is to utilize both human IBD patients and murine platelets to determine the role of the hyaluronan receptor, layilin, in platelets. This receptor is downregulated in IBD patients, correlating to the well-documented platelet dysfunction in patients. Preliminary results show that inhibiting this receptor results in loss of platelet aggregation, spreading, and HA degradation. The central hypothesis of this proposal is that dysregulation of platelet-driven HA metabolism enhances recruitment and activation of CD44-expressing cells, such as leukocytes, into the intestinal microvasculature. The rationale for this project is that layilin could be a novel target for treatment of platelet dysregulation in chronic inflammatory diseases. It may be acting as a negative regulator for platelet activation based on our preliminary results. The central hypothesis will be tested by examining two specific aims: 1) to determine how layilin mediates cell signaling driving platelet activation and 2) to determine the mechanism by which layilin influences inflammation in a murine model of colitis. This approach is innovative because it targets the understudied receptor in hyperactive platelets, a cell type not extensively investigated in disease progression of IBD. In the final aim, we will also be utilizing platelet specific LAYN KO (PF4-Cre LAYNfl/fl) and WT mice to produce a novel murine model for ulcerative colitis. The proposed research is significant because we anticipate this research to develop a non-invasive treatment for thromboinflammatory diseases.

抽象的 炎症性肠病 (IBD) 的特点是结肠内不适当的免疫细胞浸润 这种疾病的发病率逐年增加。目前尚无治愈方法，患者只能通过以下方式缓解症状 手术和免疫抑制剂。细胞外基质成分透明质酸 (HA) 被合成为 炎症期间的电缆状结构，充当招募的白细胞的附着位点。血小板结合 这些电缆会降低 HA 的性能，并且在 IBD 期间会丧失代谢 HA 的能力。这些HA片段 释放到循环中时具有促炎作用。然而，血小板如何识别HA尚不清楚。 我们的长期目标是通过靶向治疗 IBD 患者，确定 IBD 患者无创治疗的潜在药物靶点 血小板上的 HA 受体。我们之前发现，与预期相反，占主导地位的 血小板上的HA受体不是CD44，而是正在研究的受体，layilin。该提案的目的是 利用人类 IBD 患者和小鼠血小板来确定透明质酸受体 Layilin 在 血小板。该受体在 IBD 患者中下调，与有据可查的血小板功能障碍相关 在患者中。初步结果表明，抑制该受体会导致血小板聚集、扩散、 和HA降解。该提案的中心假设是血小板驱动的 HA 失调 新陈代谢增强了表达 CD44 的细胞（例如白细胞）进入肠道的募集和激活 微血管系统。该项目的基本原理是莱伊林可能成为治疗血小板的新靶点 慢性炎症疾病的失调。它可能充当血小板活化的负调节剂 根据我们的初步结果。将通过检查两个具体目标来检验中心假设：1） 确定layilin如何介导驱动血小板活化的细胞信号传导，并2)通过以下方式确定其机制： 其中莱伊林影响小鼠结肠炎模型中的炎症。这种方法是创新的，因为它的目标是 活跃血小板中尚未被研究的受体，这种细胞类型在疾病进展中尚未得到广泛研究 炎症性肠病。在最终目标中，我们还将利用血小板特异性 LAYN KO (PF4-Cre LAYNfl/fl) 和 WT 小鼠 建立了一种新型的溃疡性结肠炎小鼠模型。拟议的研究意义重大，因为我们预计 这项研究旨在开发一种针对血栓炎症性疾病的非侵入性治疗方法。