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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

炎症性肠病 (IBD) 是一种无法治愈的疾病，每年影响约 300 万美国患者 IBD 的数量不断增加，它由两种密切相关的疾病组成：克罗恩病 (CD) 和溃疡病。结肠炎 (UC)，通常在生命的前三十年出现，导致无情的炎症破坏 IBD 患者的胃肠道血液处于高凝状态。和血栓栓塞 (TE)，其中危及生命的血凝块脱落并通过血流流动阻塞其他血管是 IBD 死亡的最重要原因，这种风险增加在 3 至 15 之间。尸检研究报告，血栓形成影响高达 40% 的患者。 IBD 患者和 25% 患有血栓事件的患者目前的治疗方案有致命的结果。不能解决血栓形成风险，并且类固醇的广泛使用除了其经典作用外还增加了风险。止血，血小板已成为免疫反应的新型调节剂，是重要的驱动因素临床报告表明血小板异常与 IBD 相关。活动、严重程度和血栓形成风险，但是导致血小板增加的分子途径 IBD 的反应性和血栓形成尚未得到充分研究，该提案的意义和创新性尚未得到充分研究。 IBD 中血小板转录发生过度激活的假设已被鉴定我们将使用C型凝集素layilin作为血小板活化和血栓形成的新型调节剂。互补的临床、体外和体内方法，独特的患者组织资源和专业知识人类血小板和微血管内皮细胞，以及最先进的测序技术， CRISPR/Cas9 技术和活体显微镜将严格检验这一假设。确定血小板活化调节因子（包括莱伊林）在活动性和非活动性疾病期间的作用 IBD 和对疾病结果的贡献将确定 Layilin 如何调节血小板活化，定义下游激活途径，并识别介导血小板粘附到新的、具体目标 3 将确定如何靶向下游的途径。血小板中的莱伊林可改善结肠炎期间的炎症和血栓形成。 1) 确定血小板的转录变化如何导致 IBD 炎症和血栓形成，2) 确定由layilin介导的血小板活化的下游调节因子，3)确定是否靶向失调的血小板通路激活可改善小鼠结肠炎的炎症和血栓形成。该提案中产生的结果将显着增加我们对高反应性血小板如何有助于 IBD 的病理生理学研究。