The Role of Layilin as a Novel Regulator of Platelet Activation and Thromboinflammation

Layilin 作为血小板活化和血栓炎症的新型调节剂的作用

• 批准号: 10638243
• 负责人: Aaron Christopher Petrey
• 金额: $ 66.51万
• 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: 2023-06-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638243
• 关键词: Abnormal Platelet; Address; Adhesions; Adhesives; Affect; Agonist; Alpha Granule; American; Atherosclerosis; Autopsy; Biological Assay; Biological Response Modifiers; Biology; Blood; Blood Platelets; Blood Vessels; Blood coagulation; C Type Lectin Receptors; C-Type Lectins; CD44 Antigens; CRISPR/Cas technology; Cardiovascular Diseases; Cause of Death; Cell Adhesion; Cell surface; Cells; Clinical; Colitis; Complex; Crohn' s disease; Data; Development; Disease; Disease Outcome; Disease model; Effector Cell; Event; Fatal Outcome; Functional disorder; Gastrointestinal tract structure; Gene Expression; Gene Expression Profiling; General Population; Genetic; Genetic Transcription; Glycosaminoglycans; Guanosine Triphosphate; Hemostatic function; Homeostasis; Human; Hyaluronan; Immune; Immune response; Immunology; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Integrins; Intestinal Diseases; Leukocytes; Life; Ligands; Link; Mediating; Metabolism; Molecular; Monomeric GTP-Binding Proteins; Mucous Membrane; Mus; Outcome; Pathogenesis; Pathway interactions; Patients; Platelet Activation; Play; Predisposition; Public Health; Reporting; Research; Resources; Risk; Role; Sepsis; Severities; Severity of illness; Signal Transduction; Steroids; Stream; Structure; Surface; Techniques; Testing; Thromboembolism; Thrombophilia; Thrombosis; Tissues; Travel; Treatment Protocols; Ulcerative Colitis; Vascular Endothelial Cell; Venous Thrombosis; Work; burden of illness; gut inflammation; human disease; improved; in vivo; inflammatory marker; inhibitor; innovation; intravital microscopy; mortality; mouse model; murine colitis; novel; novel strategies; novel therapeutics; pharmacologic; preservation; receptor; response; scaffold; therapeutic target; thromboinflammation; thrombotic; transcriptome sequencing; venous thromboembolism

A condition with no cure, inflammatory Bowel Disease (IBD) affects ~3 million patients in the US each year with the number ever increasing. IBD consists of two closely related disorders, Crohn’s disease (CD) and ulcerative colitis (UC), and usually manifest in the first three decades of life leading to relentless inflammatory destruction of the gastrointestinal tract in susceptible individuals. The blood of IBD patients exists in a hypercoagulable state and thromboembolism (TE), in which life-threatening blood clots break off and travel through the blood stream to block other vessels, is the most significant cause of mortality in IBD. This increased risk is between 3- and 15- fold during inactive and active disease respectively. Necropsy studies report thrombosis affects up to 40% of IBD patients, and 25% of patients suffering a thrombotic event have a fatal outcome. Current treatment regimens do not address thrombosis risk, and widespread steroid use increases risk. In addition to their classical role in hemostasis, platelets have emerged as novel regulators of the immune response that act as significant drivers of inflammation and tissue damage. Clinical reports suggest that platelet abnormalities associate with IBD activity, severity, and thrombosis risk, however molecular pathways responsible for increased platelet reactivity and thrombosis in IBD are not well studied. This proposal tests the significant and innovative hypothesis that platelets become transcriptionally altered toward hyperactivation in IBD and identified the C-type lectin layilin as a novel regulator of platelet activation and thrombosis. We will employ complementary clinical, in vitro, and in vivo approaches, a unique resource of patient tissues and expertise with human platelets and microvascular endothelial cells, along with state-of-the-art sequencing techniques, CRISPR/Cas9 technology, and intravital microscopy to rigorously test this hypothesis. Specific Aim 1 will determine how regulators of platelet activation, including layilin, are altered during active and inactive disease in IBD and contribute to disease outcomes. Specific Aim 2 will determine how layilin regulates platelet activation, define downstream activation pathways, and identify receptors and ligands mediating platelet adhesion to novel, inflammatory hyaluronan-cable matrices. Specific Aim 3 will establish how targeting pathways downstream of layilin in platelets improves inflammation and thrombosis during colitis. Successful completion of these aims will 1) determine how transcriptional changes in platelets contribute to inflammation and thrombosis in IBD, 2) determine downstream regulators of platelet activation mediated by layilin, 3) establish whether targeting dysregulated platelet activation pathways in improves inflammation and thrombosis in murine colitis. Data generated in this proposal will significantly increase our understanding of how the hyperreactive platelets contribute to the pathophysiology of IBD.

没有治愈，炎症性肠病（IBD）的疾病每年影响约300万患者 数字不断增加。 IBD由两种密切相关的疾病组成，克罗恩病（CD）和溃疡 结肠炎（UC），通常在生命的前三十年中表现出远程炎症破坏 易感性个体的胃肠道。 IBD患者的血液存在于高凝状态 和血栓主义（TE），其中威胁生命的血块破裂并通过血液流过 阻止其他船只，是IBD死亡率的最重要原因。这种增加的风险在3-至15之间 分别在非活动和活跃疾病期间折叠。尸检研究报告血栓形成影响多达40％ IBD患者，有25％的患者患有血栓性事件的患者有致命的结果。当前的治疗方案 请勿应对血栓形成风险，而宽度的立体使用会增加风险。除了他们在 止血，血小板已成为免疫响应的新型调节剂，起着重要驱动力的作用 炎症和组织损伤。临床报告表明，血小板异常与IBD相关 活性，严重程度和血栓形成风险，但是分子途径导致血小板增加 IBD中的反应性和血栓形成并不是很好。该提案测试了重要和创新的 假设血小板在转录中朝着IBD中的过度激活变化并确定 C型凝集素丁基蛋白是血小板激活和血栓形成的新调节剂。我们将雇用 完全临床，体外和体内方法，是患者组织的独特资源和专业知识 人血小板和微血管内皮细胞以及最新的测序技术， CRISPR/CAS9技术和浸润显微镜严格检验该假设。具体目标1将 确定在活性疾病和非活性疾病中如何改变血小板激活的调节剂 IBD并为疾病结局做出贡献。特定的目标2将确定lyilin如何调节血小板激活， 定义下游激活途径，并识别介导血小板粘合剂的受体和配体， 炎性透明质酸茶矩阵。特定的目标3将确定如何将瞄准途径如何下游 血小板中的碱性蛋白可以改善结肠炎期间的注射和血栓形成。这些目标的成功完成将 1）确定血小板的转录变化如何有助于IBD的注射和血栓形成，2） 确定lyilin介导的血小板激活的下游调节剂，3）确定是否靶向 血小板激活途径失调可改善鼠结肠炎的注射和血栓形成。数据 在此提案中产生的将大大提高我们对高反应性血小板的理解 有助于IBD的病理生理。