Platelet-hyaluronan interactions as regulators of inflammation and thrombosis

血小板-透明质酸相互作用作为炎症和血栓形成的调节剂

基本信息

批准号：
10080750
负责人：
Aaron Christopher Petrey
金额：
$ 24.9万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080750
关键词：
Abnormal Platelet Acute Lung Injury Address Animals Atherosclerosis Biochemical Biochemistry Biogenesis Biology Biomedical Research Blood Platelets Blood Vessels Bone Marrow Cardiovascular Diseases Cells Chronic Coagulation Process Colitis Cues Data Defect Deposition Development Development Plans Disease Effector Cell Elements Endothelium Environment Enzymes Experimental Models Extracellular Matrix Foundations Functional disorder Funding Future Glycobiology Glycosaminoglycans Hemostatic function Human Hyaluronan Hyaluronidase Immune Immune response Infiltration Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Investigation Leukocytes Life Mediating Megakaryocytes Mentors Mentorship Mission Modeling Molecular Mus National Heart, Lung, and Blood Institute Outcome Pathogenesis Pathologic Pathway interactions Patients Pattern Platelet Activation Post-Translational Regulation Postdoctoral Fellow Prevention Productivity Proteins Public Health Recombinants Records Research Research Personnel Research Priority Resources Role Sentinel Sepsis Severities Severity of illness Signal Transduction Solid Specimen Structure Surveys Technical Expertise Testing Thrombosis Tissues Training Transcriptional Regulation Transfusion Translating Translational Regulation Translational Research base career career development chronic inflammatory disease human disease inflammatory disease of the intestine inflammatory marker insight lens mouse model novel platelet function pre-doctoral programs receptor binding recruit response sensor skills training supportive environment thromboinflammation vascular factor

项目摘要

PROJECT SUMMARY Title: Platelet-hyaluronan interactions as regulators of inflammation and thrombosis Key Words: Platelets, hyaluronan, inflammation, thrombosis, Hyaluronidase-2 The Candidate is a postdoctoral fellow and young investigator dedicated to developing an academic career focused on investigating the intersection of inflammation and thrombosis through an extracellular matrix lens as an underlying mechanism in chronic inflammatory disease. With a strong background in extracellular matrix biology, and biochemistry, the candidate has developed new expertise in mechanistic platelet biology and the use of mouse models to conduct the proposed studies. The Career Development Plan described in the proposal outlines 2 years of mentored training including technical skill training and career development activities to promote the successful transition to independence and future funding. The candidate's Mentor and Co-Mentor have proven track-records of excellent, translational research productivity and successful mentorship. Research Plan: Platelets are specialized cells essential for hemostasis that also function as crucial effectors capable of modulating inflammatory and immune responses. These innate immune sensors continually survey their environment and discriminate between homeostatic and danger signals. Components of the extracellular matrix (ECM) are detected by platelets as `damage associated-molecular patterns' (DAMPS) and can elicit pro- inflammatory responses. One such ECM component, the glycosaminoglycan hyaluronan (HA), acquires a unique `cable-like' structure in response to inflammation. Our lab has shown that: (1) HA cable formation precedes inflammatory cell infiltration, (2) HA cables produced by the endothelium recruit leukocytes, (3) Hyal-2 is required for platelet biogenesis, and (4) the platelet-derived enzyme Hyal-2 degrades HA cables. Our preliminary observations show that mice with systemic Hyal-2 deficiency display increased inflammation and disease severity in a murine model of colitis. Importantly, these findings are significantly reduced by transfusion of wild- type platelets. We believe that these results translate an entirely new mechanism by which platelet-HA interactions regulate inflammation and will provide new insights into inflammatory pathways generalizable to other inflammatory diseases. Based on our preliminary data we propose the overarching hypothesis that: Dysregulation of vascular HA due to platelet Hyal-2 deficiency promotes inflammation and thrombosis. We will evaluate the mechanism(s) by which platelet-hyaluronan interactions regulate inflammation, thrombosis, and the underlying mechanism in which inflammation can alter megakaryocyte development and platelet biogenesis by using a unique resource of patient-derived specimens and mouse models of inflammation. This application builds on robust preliminary data, a personal track record of productive research, an extremely supportive environment, an advisory panel with national recognition for their expertise in inflammation, thrombosis, and translational research, and a fully committed department. Together these elements will support and facilitate the training and advancement of the PI to a successful career of independent biomedical research.

项目概要标题：血小板-透明质酸相互作用作为炎症和血栓形成的调节剂关键词: 血小板, 透明质酸, 炎症, 血栓形成, 透明质酸酶-2 候选人是一名博士后研究员和年轻研究员，致力于发展学术事业专注于通过细胞外基质透镜研究炎症和血栓形成的交叉点慢性炎症性疾病的潜在机制。具有深厚的细胞外基质背景生物学和生物化学，候选人在机械血小板生物学和使用小鼠模型进行拟议的研究。提案中描述的职业发展计划概述了 2 年的指导培训，包括技术技能培训和职业发展活动，以促进向独立和未来融资的成功过渡。候选人的导师和共同导师拥有出色的转化研究生产力和成功指导的良好记录。研究计划：血小板是止血所必需的特殊细胞，也可作为关键效应器发挥作用调节炎症和免疫反应。这些先天免疫传感器不断地调查它们的环境并区分稳态信号和危险信号。细胞外基质的成分 (ECM) 被血小板检测为“损伤相关分子模式”(DAMPS)，并且可以引发亲炎症反应。其中一种 ECM 成分，糖胺聚糖透明质酸 (HA)，具有独特的特性对炎症做出反应的“电缆状”结构。我们的实验室表明： (1) HA 电缆形成先于炎症细胞浸润，(2) 内皮募集白细胞产生的 HA 电缆，(3) 需要 Hyal-2 (4) 血小板衍生酶 Hyal-2 降解 HA 电缆。我们的初步观察结果表明，患有全身性 Hyal-2 缺陷的小鼠表现出炎症和疾病增加小鼠结肠炎模型的严重程度。重要的是，通过输注野生动物，这些结果显着减少。型血小板。我们相信这些结果转化了血小板-HA 的全新机制相互作用调节炎症，并将为可推广到的炎症途径提供新的见解其他炎症性疾病。根据我们的初步数据，我们提出总体假设：血小板 Hyal-2 缺乏导致血管 HA 失调，促进炎症和血栓形成。我们将评估血小板-透明质酸相互作用调节炎症、血栓形成、以及炎症改变巨核细胞发育和血小板的潜在机制通过使用患者来源的标本和炎症小鼠模型的独特资源进行生物发生。这应用程序建立在可靠的初步数据、富有成效的研究的个人记录、极其支持性环境，一个在炎症方面的专业知识得到国家认可的咨询小组，血栓形成、转化研究，以及一个全力投入的部门。这些要素将共同支持促进 PI 的培训和晋升，使其在独立生物医学研究领域取得成功。